HELLO AND WELCOME TO DAY ONE
OF OUR WORKSHOP ON CEREBRAL
PALSY.
MY NAME IS THERESA CRUZ I'M THE
DIRECTOR OF THE NATIONAL CENTER
FOR MEDICAL REHABILITATION
RESEARCH AT THE NATIONAL
INSTITUTE OF CHILD HEALTH AND
HUMAN DEVELOPMENT OR NICHD.
AND WE HAVE THE PLEASURE OF
CO-HOSTING THIS WORKSHOP TO
EXAMINE THE PROGRESS AND
CEREBRAL PALSY RESEARCH SINCE
2017 WITH OUR PARTNERS, THE
NATIONAL INSTITUTE OF
NEUROLOGICAL DISORDERS AND
STROKE.
NINDS.
AND YOU WILL BE HEARING MORE
FROM STAFF FROM BOTH INSTITUTES
OVER THE NEXT TWO DAYS.
BEFORE WE BEGIN, I WOULD LIKE TO
ADDRESS A FEW HOUSEKEEPING
ITEMS.
IF I CAN HAVE THE NEXT SLIDE,
THANK YOU.
WE'RE USING A ZOOM WEBINAR AND
THIS IS ALSO SIMULTANEOUS ON THE
NIH VIDEO CAST SYSTEM.
THE MEETING IS BEING RECORDED
AND WILL BE ARCHIVED FOR FUTURE
REFERENCE.
THE AUDIENCE CAN ASK QUESTIONS
AND WE DO ENCOURAGE YOU TO ASK
QUESTIONS AND PARTICIPATE BY
TYPING THEM INTO THE Q&A BOX.
WE HAVE MODERATORS WHO WILL BE
COLLECTING THEM DURING THE
TALKS, AND SO DON'T FEEL LIKE
YOU NEED TO WAIT WHEN THE SPIRIT
MOVES YOU, PLEASE ENTER YOUR
QUESTION AND WE'LL BRING THEM
OUT AT PANEL DISCUSSIONS
SCHEDULED OVER THE NEXT TWO
DAYS.
WE ARE COMBINING LIVE
DISCUSSIONS WITH PRE-RECORDED
TALKS.
SO AGAIN, USING THE Q&A FUNCTION
IS THE BEST WAY TO GET THOSE
TOPICS INTO DISCUSSION.
WE WILL NOT BE PAUSING TO
ADDRESS CLARIFYING QUESTIONS
AFTER EACH TALK.
THERE IS LIVE CAPTIONING ON THE
NIH VIDEO CAST AND SO IF YOU ARE
NOT SEEING THAT IN THE ZOOM, YOU
WOULD DIRECT YOU THERE.
AND USE THE LIVE FEEDBACK LINK
THERE TO PROVIDE YOUR QUESTIONS.
AND IF YOU ARE HAVING
ACCESSIBILITY ISSUES, PLEASE
E-MAIL DAMON CANE HIS E-MAIL ON
THE SLIDE YOU SHOULD SEE NOW.
SO WITH THOSE HOUSEKEEPING
ISSUES OUT OF THE WAY, IT IS MY
PLEASURE TO INTRODUCE OUR FIRST
SET OF TALKS.
FIRST WE WILL HEAR FROM Dr.
DIANA BIANCHI THE DIRECTOR OF
NICHD WHO WILL GIVE YOU A MUCH
MORE POLISHED WELCOME AND SET
THE STAGE FOR THE WORKSHOP.
NEXT YOU WILL BE HEARING FROM ME
AGAIN AND IN A DIFFERENT OUTFIT
AND A HAIRCUT.
AND I'LL BE PRESENTING AN
ANALYSIS OF THE CEREBRAL PALSY
RESEARCH PORTFOLIO AT NIH.
AFTER THAT, WE WILL HEAR A TALK
FROM RACHEL BYRNE, THE EXECUTIVE
DIRECTOR AT THE CEREBRAL PALSY
FOUNDATION AND SHE'S A PHYSICAL
THERAPIST BY TRAINING AND WILL
BE TALKING ABOUT SOME RECENT
ACTIVITIES BY CPF AND THEN I'M
VERY EXCITED TO HEAR FROM
CAYDANCE ANDERSON, A YOUNG WOMAN
WHO WILL PROVIDE THE VOICE OF
THE PARTICIPANT.
IT'S REALLY A PLEASURE TO
KICKOFF THESE MEETINGS WITH THE
PERSPECTIVE OF SOMEONE WHO IS
PARTICIPATING IN RESEARCH
PROTOCOLS AND HOPEFULLY THAT
WILL FRAME THE RESEARCH TALKS
THAT FOLLOW FOR THE REST OF
TODAY AND TOMORROW.
WITHOUT FURTHER DELAY, THANK YOU
AND LET'S GET STARTED.
>> GOOD MORNING.
AND WELCOME TO ALL OF YOU, I'M
Dr. DIANA BIANCHI, DIRECTOR
THE EUNICE KENNEDY SHA ARRIVER
NATIONAL INSTITUTE OF CHILD
HEALTH AND HUMAN DEVELOPMENT
OTHERWISE KNOWN AS NICHD.
IT'S MY PLEASURE TO WELCOME YOU
ALL TO TODAY'S WORKSHOP.
WHICH WAS PLANNED JOINTLY BY THE
STAFF AT NICHD AND THE NATIONAL
INSTITUTE OF NEUROLOGICAL
DISORDERS AND STROKE, OTHERWISE
KNOWN AS NINDS.
THE NIH STRATEGIC PLAN FOR
CEREBRAL PALSY RESEARCH,
RELEASED IN 2017, WAS DESIGNED
AS A TEN-10 PLAN TO GUIDE
CEREBRAL PALSY RESEARCH AREAS.
THESE INCLUDE THE UNDERSTANDING
OF THE UNDERLYING CAUSES AND
PATHO PHYSIOLOGY, IMPROVING
DIAGNOSIS, IDENTIFYING POTENTIAL
PREVENTION STRATEGIES AND
THERAPEUTIC INTERVENTIONS AND
IMPROVING THE QUALITY OF LIFE
FOR PEOPLE WITH CEREBRAL PALSY.
THE GOAL OF TODAY'S WORKSHOP IS
TO EXPLORE PROGRESS MADE IN THE
FIELD OF CEREBRAL PALSY
RESEARCH, SINCE THE PUBLICATION
OF THE NIH STRATEGIC PLAN FOR
CEREBRAL PALSY IN 2017.
THIS 2017 STRATEGIC PLAN WAS
DEVELOPED THROUGH A SERIES OF
WORKSHOPS WITH INPUT FROM THE
ADVOCACY AND PATIENT
COMMUNITIES.
I'M PLEASED TO SEE
REPRESENTATIVES FROM SEVERAL
PATIENT ORGANIZATIONS ATTENDING
TODAY'S MEETING AS WELL AS PAR
PARTICIPATING IN THE AGENDA.
AS THE DIRECTOR OF NICHD, ONE
KEY COMPONENT THAT I'VE ADDED TO
MANY OF OUR SCIENTIFIC MEETINGS,
IS THE RESEARCH, PARTICIPANT PAR
PERSPECTIVE OTHERWISE KNOWN AS
THE VOICE OF THE PARTICIPANT.
OBTAINING INPUT ON BOTH THE
LIVED EXPERIENCES OF PEOPLE WITH
CEREBRAL PALSY, AND AS WELL AS
THEIR PERSONAL EXPERIENCES
PARTICIPATING IN RESEARCH.
OUR VERY INFORMATIVE.
TODAY I'M PARTICULARLY DELIGHTED
TO SEE THAT THE WORKSHOP WILL
BEGIN WITH A CONVERSATION
BETWEEN CAYDANCE ANDERSON, A
YOUNG WOMAN PARTICIPATED IN A
REHABILITATION RESEARCH STUDY
AND RACHEL BYRNE, OF THE
CEREBRAL PALSY FOUNDATION.
AS A MEDICAL GENETICIST WITH A
ACTIVE LAB AT NIH, I'M ALSO
PARTICULARLY INTRIGUED BY THE
RESEARCH FINDINGS THAT THERE ARE
CAUSE TIVE GENOME VARIANTS IN AS
MANY AS A THIRD OF THE PEDIATRIC
CASES OF CEREBRAL PALSY.
NICHD CONTINUES TO SUPPORT THIS
PARADIGM SHIFTING RESEARCH THAT
IS BEING PERFORMED AT THE
CLINIC.
OVER THE NEXT TWO DAYS, WE'RE
GOING TO HEAR FROM NIH
RESEARCHERS AND TRAINEES WHO
WILL HIGHLIGHT ADVANCES IN BASIC
TRANSLATIONAL AND CLINICAL
RESEARCH IN CEREBRAL PALSY.
WE HAVE LEFT PLENTY OF TIME FOR
DISCUSSION FOLLOWING THE
PRESENTATIONS TO TALK ABOUT THE
NEW AND PERSISTENT GAPS AND
OPPORTUNITIES IN THE RESEARCH
PORTFOLIO.
WE HOPE THAT YOU ACTIVELY ENGAGE
THROUGH THE WEBINAR, QUESTION
AND ANSWER FEATURE, TO MAKE THIS
WORKSHOP AS INTERACTIVE AS
POSSIBLE DESPITE THE VIRTUAL
FORMAT.
THIS IS AN IMPORTANT WORKSHOP
THAT WILL ACT AS A CHECK-IN FOR
PROGRESS AT THE HALFWAY POINT OF
THE STRATEGIC PLAN.
THE NEXT TALK IS GOING TO BE BY
Dr. THERESA CRUZ, WHO IS THE
DIRECTOR OF THE NATIONAL CENTER
FOR MEDICAL REHABILITATION
RESEARCH AT NICHD AND SHE'S
GOING TO BRIEFLY REVIEW THE
INVESTMENTS THAT HAVE BEEN MADE
BY NIH IN CEREBRAL PALSY
RESEARCH.
FOLLOWING TODAY'S MEETING, A
SUMMARY WILL BE POSTED TO THE
NIH WEBSITE AND WE HOPE THAT IT
WILL BE USED BY THE RESEARCH
COMMUNITY TO MOVE THE FIELD
FORWARD.
I WOULD LIKE TO CONCLUDE BY
THANKING MY COLLEAGUES AT NINDS
FOR THEIR LEADERSHIP AND
PLANNING THIS WORKSHOP.
THE STAFF AT NICHD, WHOM YOU
WILL BE SEEING AND HEARING FROM
THROUGHOUT THE WORKSHOP, THE
SPEAKERS WHO HAVE SHARED THEIR
TIME AND EXPERTISE, AND OF
COURSE, ALL OF YOU, THE
ATTENDEES.
AS I SAID BEFORE, I REALLY DO
HOPE THAT YOU WILL BE ENGAGE IN
THE CHATBOX VIA THE QUESTION AND
ANSWER FEATURES.
AND CONTRIBUTE TO THE OVER ALL
DISCUSSION.
THANK YOU FOR YOUR INTEREST IN
THIS AREA AND I HOPE THAT YOU
ALL HAVE A VERY PRODUCTIVE
MEETING.
TAKE CARE.
>> GOOD MORNING.
MY NAME IS THERESA CRUZ I'M THE
DIRECTOR THE NATIONAL CENTER FOR
MEDICAL REHABILITATION RESEARCH
AT NICHD.
I WANT TO THANK YOU FOR THE
OPPORTUNITY TO TALK TO YOU TODAY
A LITTLE BIT ABOUT THE NIH
CEREBRAL PALSY RESEARCH
PORTFOLIO.
AND I'M SPEAKING ON BEHALF OF
QUITE A FIE PEOPLE WHO PUT MOST
OF THE WORK INTO THIS SO I WANT
TO THANK RACHEL ANDERSON, CAROLE
LONG, AND THE GROUP AT NINDS.
I WOULD ALSO LIKE TO THANK MY
COLLEAGUES ON THIS WORKSHOP
PLANNING COMMITTEE WHO YOU WILL
BE HEARING FROM THROUGHOUT THE
NEXT TWO DAYS OF THE WORKSHOP.
I'LL ALSO START WITH A QUICK
DISCLAIMER THAT WE'RE GOING TO
BE PRESENTING DATA THAT IS
PUBLICLY AVAILABLE AND THAT WE
HAVE USED THE R CDC CEREBRAL
PALSY CATEGORY FOR MOST OF THIS
PRESENTATION AND WE'VE ALSO
PULLED DATA FROM
CLINICALTRIALS.GOV AND WE'RE
FOCUS ONG THE EXTRAMURAL
RESEARCH FUNDING BECAUSE THAT
WAS THE TARGET AUDIENCE FOR THE
2017 CEREBRAL PALSY STRATEGIC
PLAN.
THIS DATA IS NOT PERFECT SO
THERE ARE A FEW TIMES WHERE I
POINT OUT CAVEATS TO HOPEFULLY
GIVE YOU A MORE ACCURATE AND
COMPLETE PICTURE.
OF THE WORK THAT NIH IS FUNDING
IN CEREBRAL PALSY.
FIRST I'D LIKE TO START OUT BY
SHOWING YOU THE INCREASE IN
FUNDING FOR CEREBRAL PALSY FROM
BEFORE THE TIME OF THE 2017
STRATEGIC PLAN, THROUGH TODAY.
AND YOU CAN SEE THAT THERE ARE
TWO MAJOR FUNDERS OF CEREBRAL
PALSY RESEARCH.
THE NICHD, NATIONAL INSTITUTES
OF CHILD HEALTH AND HUMAN
DEVELOPMENT, AND NINDS, THE
NATIONAL INSTITUTE ON
NEUROLOGICAL DISORDERS AND
STROKE.
BUT THERE ARE ALSO MANY OTHER
INSTITUTES AT NIH THAT SUPPORT
CEREBRAL PALSY RESEARCH AND I'D
LIKE TO ACKNOWLEDGE THEIR
CONTRIBUTIONS.
THERE'S ALSO BEEN A STEADY
INCREASE OF ABOUT $20 MILLION TO
START THIS 10 YEARS AGO TO
AROUND $30 MILLION TODAY.
YOU WILL SEE THAT THERE'S THIS
KIND OF BUM IN 2020 DUE TO A
LARGE COVID SUPPLEMENT OF
$3 MILLION THAT WAS AWARDED TO
OUR MATERNAL FETAL MEDICINE UNIT
COORDINATING COMMITTEE,
COORDINATING CENTER AND THE REST
OF THAT GRANT WAS NOT CODED FOR
CEREBRAL PALSY.
SO, YOU SHOULDN'T THINK OF THIS
AS A DROP FROM 2020 BUT RATHER A
NICE STEADY INCREASE FROM 2013
THROUGH 2021.
THIS IS IN MILLIONS OF DOLLARS
IN CEREBRAL PALSY FUNDING.
THE OTHER THING WE CAN LOOK AT
IS THE NUMBER OF GRANTS THAT ARE
IN CEREBRAL PALSY RESEARCH AS
WELL AS THE TYPES OF RESEARCH
THAT THOSE GRANTS ARE
SUPPORTING.
SO HERE AGAINST WE SEE THIS NICE
TREND OF INCREASING FROM 2013
THROUGH THE TIME OF PLAN WHICH
IS 2018 AND BEYOND.
SO WE'VE GONE FROM AROUND 55
GRANTS TO OVER 70 GRANTS AND IN
CEREBRAL PALSY RESEARCH.
TO ME, WHAT'S PARTICULARLY
ENCOURAGING ABOUT THIS SLIDE IS
THAT WE'VE GONE FROM SIX
CLINICAL TRIALS TO 18 CLINICAL
TRIALS.
SO, THIS IS A THREE-FOLD
INCREASE IN THE A LOT OF
INTERVENTIONAL RESEARCH FOR
PEOPLE WITH CEREBRAL PALSY.
SOME OF THAT IS GOING TO BE AN
ARTIFACT OF CHANGING
DEFINITIONS, BUT I DO THINK THAT
THE TREND TOWARDS MORE TREATMENT
OPTIONS IS WHAT WE'RE SEEING IN
THIS DATA.
SO THAT IS OUR 20,000-FOOT VIEW
OF THE CEREBRAL PALSY RESEARCH
PORTFOLIO.
NOW, DIGGING MORE INTO THE
STRATEGIC PLAN THAT WAS
PUBLISHED IN 2017, THERE WERE
THREE PRIORITY AREAS
HIGHLIGHTED.
THE FIRST BASIC AND
TRANSLATIONAL RESEARCH AND IT
HAS HAD FOUR OBJECTIVES
UNDERNEATH IT, I'M NOT GOING TO
READ THEM ALL HERE.
YOU CAN SEE THEM AND YOU HAVE
ACCESS TO THAT PLAN.
THE SECOND RESEARCH PRIORITY WAS
CLINICAL RESEARCH AND WE HAD
FIVE OBJECTS UNDERNEATH IT AND
THE THIRD PRIORITY AREA IS
WORKFORCE DEVELOPMENT.
NOW, RATHER THAN TAKE ALL OF
THOSE 70 GRANTS AND PUT THEM
INTO EACH OF THESE OBJECTIVES
AND PRIORITY AREAS, THAT PROVED
REALLY DIFFICULT BECAUSE THERE
WAS A LOT OF OVERLAP IN THESE
TOPICS.
SO WHAT WE'VE INSTEAD DECIDED TO
DO IS TO SHOW YOU EXAMPLES OF
FOR THE MOST PORT, RO1
APPLICATION AWARDS THAT ARE
BEING FUNDED UNDER EACH OF THESE
OBJECTIVES.
SO, FIRST, IN PRIORITY AREA 1,
WE HAVE EXAMPLES OF BASIC AND
TRANSLATIONAL RESEARCH.
AGAIN, I'M NOT GOING TO READ ALL
THE TITLES, BUT YOU CAN SEE WE
ARE COVERING MECHANISMS, BOTH
THROUGH ANIMAL MODELS AND IN
HUMAN RESEARCH.
NEW TECHNIQUES IN NEUROIMAGING,
BIOMARKERS, AND AS WELL AS NEURO
PLASTICITY BOTH IN PEOPLE AT
RISK FOR CEREBRAL PALSY AND WITH
CEREBRAL PALSY DIAGNOSIS, OUR
SECOND IS CLINICAL RESEARCH.
SO WEST OBJECTIVES OF LIVES SPAN
APPROACH, NEW TREATMENTS,
ALTERNATIVE STUDY DESIGNS, AND
MORE RESEARCH INTO METRICS AND
THE USE OF DATA SHARING.
AGAIN, I'M NOT GOING TO READ ALL
THESE TITLES, BUT WE DID WANT TO
SHOW THAT WE HAVE WORK IN
DIAGNOSTICS AND PREVENTION AND
EARLY INTERVENTION, AND
TREATMENT OF OLDER TEENS.
WE DID NOTICE THAT THERE IS A
LACK OF APPLICATIONS AND AWARDS
IN TREATMENT FOR ADULTS WITH
CEREBRAL PALSY.
SO WE'RE NOT ADDRESSING THE
ENTIRE LIFESPAN.
WE'LL TALK MORE ABOUT THAT
LATER.
BUT THAT CONTINUES TO BE A GAP
IN AN OPPORTUNITY FOR THE
RESEARCH FIELD.
WE ARE CERTAINLY INVESTIGATING
TREATMENTS AND THAT HAS COME UP
IN THE INCREASE IN THE NUMBER OF
CLINICAL TRIALS.
BECAUSE OF THE DEVELOPMENTAL
ASPECT OF CEREBRAL PALSY, WE
HAVE SEVERAL PROJECTS NOT DOING
THE TRADITIONAL RANDOMIZED
CONTROL TRIAL BUT ARE
USING OTHER STUDY DESIGNS AND
WE'VE ALSO NOTED THAT IT'S QUITE
IMPORTANT TO MAKE SURE THAT OUR
PROPERTIES OF SCALES ARE
ASSESSED AND VALIDATED FOR
PEOPLE WITH CEREBRAL PALSY.
DIGGING A LITTLE BIT FURTHER
HERE, WE WANTED TO HIGHLIGHT A
REQUEST FOR APPLICATIONS FOR
RO1s AND AT NICHD PUBLISHED IN
2020.
WE FUNDED THREE AWARDS.
ALL OF WHICH WERE IN CEREBRAL
PALSY RESEARCH.
I THINK THIS REALLY SPEAKS TO
THE STRENGTH OF THE CEREBRAL
PALSY RESEARCH COMMUNITY.
WE DID NOT PARTICULARLY
HIGHLIGHT OR SEEK TO ONLY GET
TOP-SCORING APPLICATIONS IN THIS
AREA, BUT THEY REALLY ROSE TO
THE TOP.
SO I THINK THIS BODES VERY WELL
FOR THE FUTURE OF CEREBRAL PALSY
RESEARCH.
AND THOSE AWARDS ARE HIGHLIGHTED
IN RED HERE.
WE TALKED ABOUT CLINICAL TRIALS
AND WE ARE SUPPORTING SEVERAL,
QUITE LARGE, CLINICAL TRIALS.
ONE OF THE STRUGGLES THAT THE
COMMUNITY HAS IS THE HETERO GENE
TEE OF THE CEREBRAL PALSY
DIAGNOSIS AND TREATMENT IN
RECRUITMENT.
WE WANTED TO HIGHLIGHT THAT IN
SEVERAL STUDIES.
WE ARE AIMING TO RECRUIT LARGE
NUMBERS OF PARTICIPANTS WE HAVE
A RESEARCH CONSORTIUM WAS NOT
PICKED UP IN OUR CEREBRAL PALSY
R CDC CATEGORY BUT WE DID THINK
IT WAS IMPORTANT TO HIGHLIGHT IT
IN THIS MEETING BECAUSE IT IS A
MAJOR EFFORT THAT WE ARE
UNDERTAKING AND YOU WILL HEAR
MORE ABOUT THAT TRIAL LATER ON
IN THE CONFERENCE.
SO, WE WANTED TO DIG A LITTLE
BIT MORE INTO THIS CLINICAL
TRIALS DATA BECAUSE WE KNOW THAT
IT'S IMPORTANT TO THE
STAKEHOLDER COMMUNITY.
SO WE RAN THOSE NIH-FINANCED
AWARDS THROUGH
CLINICALTRIALS.GOV TO SEE HOW
THEY ARE RECRUITING AND
REPORTING OUT TO THE COMMUNITY.
AND YOU WILL SEE THAT MOST OF
THE TRIALS THAT WE ARE
SUPPORTING, HAVE IDENTIFIED
CEREBRAL PALSY AS A DIAGNOSTIC
CATEGORY AND THEY ARE PROVIDING
INTERVENTIONS.
SO THAT'S 21 HERE.
BUT AGAIN, THERE ARE OTHER
TOPICS RELATED TO CEREBRAL PALSY
OR THAT MAY BE RISK FACTORS FOR
C.P. THAT WERE ALSO PART OF OUR
CATCHMENT AND THEN THERE ARE
SOME STUDIES THAT ARE
OBSERVATIONAL AND NOT TARGETED
TO PROVIDE THERAPY.
THE OTHER THING WE DID IS DIG A
BIT DEEPER INTO THE AGES OF THE
SUBJECTS THAT ARE BEING
RECRUITED AND TO THOSE TRIALS.
AGAIN, BECAUSE WE KNOW LIFESPAN
IS SUCH AN IMPORTANT ISSUE HERE.
WE SAW THAT THE MAJORITY OF OUR
TRIALS ARE TARGETED TOWARDS
CHILDREN AND INFANTS.
WE DID HAVE A SMALL AMOUNT,
INCLUDING ADULTS, AGES 18 AND
UP.
SO AGAIN, THIS IS AN AREA WHERE
WE COULD BE DOING BETTER AS FAR
AS THE ADULT AND AGING OF
CEREBRAL PALSY.
THIS IS MY FAVORITE SLIDE.
SO THE THIRD PRIORITY AREA IS
DEVELOPMENT OF THE CEREBRAL
PALSY RESEARCH WORKFORCE.
SO HERE I THINK WE SHOW AN
INCREDIBLE GROWTH IN THE NUMBER
OF FELLOWSHIP AWARDS AND
TRAINING AND CAREER DEVELOPMENT
FROM BEFORE THE STRATEGIC PLAN
UNTIL AFTER.
SO WE SEE THAT WE HAVE DOUBLED
THE NUMBER OF FELLOWSHIPS.
WE SEE INCREASES IN THE MENTORED
EARLY KA RO CAREER DEVELOPMENT L
AS THE NCMRR EARLY CAREER RO3s
AND WE'VE SUPPORTED DIVERSITY
SUPPLEMENT THIS IS THE AREA OF
CEREBRAL PALSY.
I THINK IT'S REALLY WONDERFUL
AND IT SHOWS WE'RE DEVELOPING A
PIPELINE OF RESEARCHER IN
CEREBRAL PALSY RESEARCH AND THAT
THEY WILL HOPEFULLY BE PUTTING
IN RO1s IN THE NEXT FIVE TO 10
YEARS.
THEY WILL BE CREATING AND
STARTING THEIR OWN LABS AND
RESEARCH CAREERS.
AS FAR AS THE AMOUNT OF MONEY
THAT GOES TO THESE TRAINING AND
KA ROAR DEVELOPMENT AWARDS, WE
HAVE INCREASED FROM 4.7% TO 6.5%
SO WE ARE PUTTING MORE MONEY
INTO THESE AWARDS AND WE'VE SEEN
20% OF THE FRIENDS IN CP ARE IN
THE FIELD OF TRAINING OR CAREER
DEVELOPMENT.
AGAIN, THIS GIVES ME GREAT
PLEASURE TO REPORT AND REALLY
HOPEFUL FOR THE DIRECTION WE
WANT TO GO IN GROWING THIS
FIELD.
WE WANTED TO HIGHLIGHT THERE ARE
MANY OTHER ACTIVITIES THAT
DIDN'T FIT QUITE INTO THE
CATEGORY OF GRANT FUNDING BUT
WERE RELATED TO THE PRIORITIES
OF THE STRATEGIC PLAN.
SO WE WANTED TO HIGHLIGHT THE
TOOL KITS PRODUCED BY THE
CEREBRAL PALSY RESEARCH NETWORK
AND AND HIGHLIGHT THE
COLLABORATION BETWEEN NINDS AND
NICHD WITH THE OFFICE OF DISEASE
PREVENTION AND LOOKING AT
PHYSICAL ACTIVITY AND THE HEALTH
OF WHEELCHAIR USERS AND CEREBRAL
PALSY WAS ONE OF THREE
DIAGNOSTIC CATEGORIES THAT WERE
FEATURED IN THE SYSTEMATIC
REVIEW AND IN THE WORKSHOP.
WE'RE QUITE PROUD OF THAT.
NINDS HAS BEEN DOING INCREDIBLE
WORK IN PUBLISHING COMMON DATA
ELEMENTS.
THERE'S A SET FOR CEREBRAL PALSY
THAT IS REGULARLY UPDATED AND
YOU WILL BE HEARING MORE FROM
THAT WORKING GROUP LATER ON IN
THE WORKSHOP.
SO, AS A PART OF OUR CONTINUED
COMMITMENT, TO GET FEEDBACK FROM
THE RESEARCH COMMUNITY, PRIOR TO
THE AGENDA SETTING FOR THIS
WORKSHOP, WE PUBLISHED A REQUEST
FOR INFORMATION.
WE WERE ASKING FOR RECENT
ADVANCES, CHALLENGES AND
OPPORTUNITIES IN ANY AREA OF
CEREBRAL PALSY RESEARCH BUT
PARTICULARLY THOSE OUTLINED IN
OUR STRATEGIC PLAN.
WE RECEIVED 25 RESPONSES WHICH
IS INCREDIBLE BECAUSE THIS IS
ONLY OUT ON THE STREET FOR A FEW
WEEKS.
AND WE HEARD FROM PEOPLE WITH
CEREBRAL PALSY, THEIR FAMILY
MEMBERS, PERMISSION TO TREAT
PEOPLE WITH CP, ACADEMIC
DEPARTMENTS IN RESEARCH
INSTITUTIONS, ORGANIZATIONS WHO
ADVOCATE FOR PEOPLE WITH CP AND
THEN ORGANIZATIONS WHO CARE FOR
PEOPLE WITH CP.
I WANT TO THANK ALL THE
RESPONDENTS FOR TAKING THE TIME
TO PROVIDE US WITH THAT INPUT.
SO SOME OF THE COMMON THEMES WE
HEARD OR ONE THAT WE NEED TO
LOOK AT THE LIFESPAN,
PARTICULARLY AGING WITH CEREBRAL
PALSY.
AND THE HEALTH NEEDS OF
ADULTHOOD CEREBRAL PALSY.
AND WE HAVE IDENTIFIED THAT THAT
CONTINUES TO BE A GAP IN OUR
PORTFOLIO.
WE ALSO NEED TO DO MORE
IMPLEMENTATION RESEARCH SO AS WE
CONDUCT CLINICAL TRIALS AND WE
FIND EFFECTIVE TREATMENTS, HOW
THEY ARE IMPLEMENTED IN CLINICAL
CARE AND HOW THEY ARE
OPERATIONALIZED TO SOMETHING
THAT ALSO NEEDS TO BE A
PRIORITY.
ONE THING THAT WAS LACKING IN
THE ORIGINAL STRATEGIC PLAN WAS
A FOCUS ON HEALTH DISPARITIES
AND INCLUSION IN CEREBRAL PALSY
RESEARCH.
SO WE DEFINITELY NEED TO DO MORE
IN LOOKING AT HEALTH DISPARITIES
WITH RESPECT TO SERVICES.
WITH RESPECT TO GENETIC
DATABASES, WE'RE SEEING MORE AND
MORE WORK IN GENOMICS RELATED TO
CEREBRAL PALSY.
AND IF WE DON'T HAVE DIVERSE
DATASETS, WE'RE NOT GOING TO BE
ABLE TO MAKE THE MOST OF THAT
INFORMATION.
AND THEN HOW DO WE REDUCE
BARRIERS TO PARTICIPATION
RESEARCH?
WE WERE ENCOURAGED TO REPAIN
WITH THE PATIENT AT OUTCOME.
WE'RE EXCITED TO HAVE A RESEARCH
PARTICIPANT LATER ON IN THE
CONFERENCE.
THERE WAS A LARGE EMPHASIS ON
CONDITIONS ASSOCIATED WITH
CEREBRAL PALSY OR SECONDARY TO
CEREBRAL PALSY THAT ALSO EFFECT
HEALTH OUTCOMES SO VISUAL
IMPAIRMENTS, PAIN, CHANGES IN
COGNITION, BONE HEALTH,
CARDIOVASCULAR HEALTH, SOCIAL
AND EMOTIONAL HEALTH SO ASIDE
FROM THE MOTOR IMPAIRMENTS OF
CP, TAKING CARE OF THE WHOLE
PERSON AND FINALLY SUPPORT FOR
THE CEREBRAL PALSY RESEARCH
WORKFORCE.
WITH THAT I WILL SAY THANK YOU.
I WILL TAKE QUESTIONS FOR THE
Q&A CHAT AND I WILL BE AVAILABLE
DURING THE FIRST BREAK WHEN WE
HAVE OUR DISCUSSION PERIOD.
THANK YOU SO MUCH.
>> HI, THANK YOU TO MUCH, I'M
RACHEL BYRNE OF THE CEREBRAL
PALSY FOUNDATION EXECUTIVE
DIRECTOR.
MY BACKGROUND IS A PHYSICAL
THERAPIST, RESEARCHER AND HEARD.
TODAY I'LL TALK TO YOU ABOUT
RESEARCH AND INTRODUCING YOU TO
A YOUNG WOMAN WHO WAS INVOLVED
IN NIH STUDY.
SO THE MISSION OF CEREBRAL PALSY
FOUNDATION IS TO BE A CATALYST
FOR CREATING POSITIVE CHANGE FOR
PEOPLE LIVING WITH CEREBRAL
PALSY AROUND THE WORLD.
WE DO THIS TO A COMMIT GROUP OF
STAFF VOLUNTEERS AND LEADERS
FROM I DO VERSE BACK GROUNDS AND
WE STRONGLY BELIEVE HOW WE THINK
AND TALK ABOUT DISABILITIES
MAKES A BIG DIFFERENCE IN HOW
OTHER PEOPLE THINK AND TALK
ABOUT DISABILITIES.
SO THE PAST 70 YEARS, THE
FOUNDATION HAS CHANGED AND
DEVELOPED ACCORDING TO THE NEEDS
OF INDIVIDUALS IN THEIR
FAMILIES.
IT WAS FIRST IMAGINED BY
DEDICATED PARENTS WHO WANTED TO
MAKE A DIFFERENCE.
WE INITIALLY FOCUSED ON FUNDING
INDIVIDUAL INVESTIGATORS IN
ACADEMIC RESEARCH, SOME OF THEM
YOU WILL HEAR OVER THE NEXT TWO
DAYS.
NOW SUPPORTING LARGE NETWORKS
AND THESE NETWORKS CAN NOW
EMBRACE THE ACADEMIC AND
IMPLEMENTATION RESEARCH THAT IS
NEEDED TO MAKE THE GREATEST
IMPACT.
SO WE HAVE FOUR MAJOR AREAS WE
WORK IN.
THE FIRST THING HEALTH, THE
SECOND EDUCATION, THE THIRD
ADVOCACY AND THE LAST ONE DESIGN
TECHNOLOGY AND WE ENABLE THIS
REAL WORLD IMPACT THROUGH THE
RESEARCH AND AN ORGANIZATION
FROM AROUND THE WORLD.
SO WE CURRENTLY HAVE OVER 100
PARTNERS THAT WE ARE WORKING
WITH.
WE HAVE 150 INDIVIDUALS IN OUR
PROGRAMS TO OUR SOCIAL MEDIA AND
COMMUNITY OUTREACH WE REACH OVER
300,000 PEOPLE AROUND THE WORLD
WEEKLY AND WE HAVE INVESTED IN
BOTH RESEARCH INNOVATION,
IMPLEMENTATION.
SO AS I SAID, WE HAVE REALLY
MOVED OUR MODEL TO NETWORKS OF
CHANGE.
THESE NETWORKS OF CHANGE ARE
DESIGNED TO IDENTIFY BIG
PROBLEMS.
AND WHAT WE'RE DOING IS WE'RE
COMMITTED TO CONNECT INDUSTRY
PARTNERS WITH RESEARCHERS, WITH
PRACTITIONERS AND ADMINISTRATORS
AND OF COURSE INDIVIDUALS AND
THEIR FAMILIES TO DRIVE THE BEST
POSSIBLE OUTCOMES.
AND SO WHEN WE THINK ABOUT THESE
NETWORKS OF CHANGE, WE LOOK AT
FOUR KEY POINTS.
FIRST BEING RESEARCH.
HOW DO WE GET INVOLVED IN
RESEARCH AND MAKE SURE THE
STAKEHOLDER DRIVEN AND OVER THE
PAST THREE YEARS, WE'VE ACTUALLY
BEEN INVOLVED IN AROUND 15
STUDIES TO HELP WITH RECRUITMENT
AND HELP WITH STUDY DESIGN.
TO THINK ABOUT THE OUT COMES
THAT FAMILIES AND INDIVIDUALS
WITH CEREBRAL PALSY WANT TO SEE.
AND THEN OF COURSE THE
INFRASTRUCTURE AND
IMPLEMENTATION THAT IS REQUIRED
TO MAKE SURE THAT THIS RESEARCH
IS GETTING TO THE INDIVIDUALS
AND THEIR FAMILIES AS SOON AS
POSSIBLE.
AT THE SAME POLICY NEEDED AND
THEN DISSEMINATION AND EDUCATION
AND DISSEMINATION AND EDUCATION
IS FOR CLINICIANS AND
RESEARCHERS AND OF COURSE IT'S
THE FAMILIES AND FOR INDIVIDUALS
TOO.
AND WE DO A LOT OF THAT THROUGH
CP RERESOURCE.ORG.
THERE ARE CEREBRAL PALSY EARLY
DETECTION INTERVENTION NETWORK
HAS BEEN AROUND FOR FIVE YEARS
AND IT INITIALLY STARTED WITH
FIVE SITES ACROSS THE COUNTRY.
THESE FIVE SITES IN THE FIRST 12
MONTHS WERE ABLE TO BRING THE
AVERAGE AGE OF DIAGNOSIS TO NINE
AND A HALF MONTHS ACROSS THE
NETWORK.
AND THIS WAS DONE THROUGH LOTS
OF DIFFERENT IMPLEMENTATION
PROCESSES, IMPLEMENTATION
SCIENCE, AND QRA INITIATIVES.
BUT OF COURSE, ONE OF OUR
BIGGEST MISSIONS OF THE
FOUNDATION IS TO THINGS IN
SINGLE ELEMENTS AND LOCALLY BUT
HOW DO WE ACTUALLY LOOK A LOT
SCALING THINGS NATIONALLY AND
INTERNATIONALLY AND HOW DO WE
ALSO MAKE SURE THAT THESE THINGS
CAN ACTUALLY HAVE SUSTAINABILITY
OVER THE LONGER PERIOD OF TIME.
SO, FIVE YEARS LATER, WE HAVE
NOW NOT ONLY EXPANDED OUR
NETWORK TO DIFFERENT SITES
ACROSS THE COUNTRY, BUT WE'VE
ALSO TRAINED MORE THAN 4,000
PROVIDERS IN EARLY DETECTION
TOOLS AND IMPLEMENTATION AND THE
CO PI ON THIS PROJECT, YOU WILL
HEAR MORE HOW SHE'S ABLE TO
UTILIZE THE NETWORK FOR ONE OF
HER STUDIES LATER ON TODAY.
WE ALSO HELD OUR FIFTH ANNUAL
EARLY CEREBRAL PALSY HEALTH
SUMMIT THIS PAST WEEKEND IN
ATLANTA, GEORGIA.
>>> SO JUST TO REITERATE WHEN
WE'RE THINKING ABOUT STAKEHOLDER
PARTICIPATION, WE WANT TO BUILD
EVIDENCE AND PRIORITIES WITH ALL
STAKEHOLDERS AND MAKE SURE WE'RE
ENGAGING STAKEHOLDERS IN
INITIATIVE DESIGN AND OUTCOMES
AND WE WANT TO MAKE SURE ALL
STAKEHOLDERS ARE ACTUALLY
PARTICIPATING IN THE RESEARCH AS
WELL.
SO IT'S MY PLEASURE TO INTRODUCE
YOU TO A YOUNG WOMAN WHO IS
RECENTLY PARTICIPATED IN AN NIH
RESEARCH STUDY AND WE ALL KNOW
THAT TEENS ARE UNDER REPRESENTED
IN RESEARCH AND IT'S IMPORTANT
FOR US TO LISTEN TO WHAT THEY
HAVE TO SAY AND IT'S SUCH A
CRITICAL TIME AS THEY TRANSITION
TO ADULTHOOD AND WE KNOW THERE'S
ACTUALLY CURRENTLY FEWER
RESEARCH OPPORTUNITIES FOR THEM
TO BE INVOLVED IN AND WE KNOW
THERE'S ALSO SOMETIMES A
BREAKDOWN IN CLINICAL CARE.
WITH THAT, I WOULD LIKE TO
INTRODUCE YOU TO CAYDANCE
ANDERSON.
A 15-YEAR-OLD WHO LIVES IN
LOUISIANA WITH HER PARENTS AND
HER TWO SISTERS.
SHE IS STARTING HER SOFT MORE
YEAR AT HIGH SCHOOL AND LOVES
MUSIC AND SINGING.
SHE HAS CEREBRAL PALSY AND WAS
FORTUNATE ENOUGH TO BE DIAGNOSED
SO SHE COULD BEGIN HER EARLY
INTERSECTION IN THE SUPPORT OF
HER FAMILY.
WHEN SHE WAS 11 YEARS OLD SHE
JOINED HER SCHOOL CROSS COUNTRY
TEAM AND SHE'S BEEN BLESSED WITH
A BEAUTIFUL SINGING VOICE THAT
ALLOWED HER TO PARTICIPATE IN
MUSIC GROUPS IN CONNECTION WITH
A NEW ORLEANS.
IN 2019 SHE JOINED AN NIH
CEREBRAL PALSY RESEARCH STUDY AT
LOUISIANA STATE UNIVERSITY WITH
Dr. NOEL MORROW.
IT FOCUSED ON POWER TRAINING AND
THROUGH THIS STUDY, CAYDANCE
REALIZED THROUGH EXERCISE SHE
CAN BE STRONGER AND MORE
SELF-SUFFICIENT AND SHE NOW
WORKS OUT WITH A TRAINER AND
ATTENDS PHYSICAL THERAPY ONCE A
WEEK SO PLEASE JOIN ME IN
WELCOMING CAYDANCE.
>> HI.
IT'S REALLY NICE TO BE HERE
TODAY.
SO, THE KIND OF CEREBRAL PALSY
THAT I HAVE IS SPASTIC DIAPLEGI
THAT EFFECTS BOTH OF MY LEGS AND
IT'S VERY MILD.
THE MAIN WAYS THAT CEREBRAL
PALSY AFFECTS ME IS WALKING AND
RUNNING ISN'T ALWAYS AS EASY FOR
ME.
MAYBE IF WE'RE DOING AN
ACTIVITY, I MIGHT NOT BE ABLE TO
PARTICIPATE IN IT, BUT JUST
THINGS LIKE THAT NORMALLY.
NORMALLY I DO PARTICIPATE IN
FIGURE OUT A WAY AROUND IT AND
AROUND TWO-YEARS-OLD I GUESS
REALIZED WHAT WAS GOING ON SO I
WAS FORT ENOUGH TO GET INTO
EARLY ON IN MY LIFE AND WHEN I
WAS GROWING UP I WENT EVERYDAY.
NOW I GO ONCE A WEEK AND I DID A
LOT OF ACTIVITIES GROWING UP AND
I WAS REALLY ACTIVE IN SCHOOL
AND IN SPORTS AND JUST THINGS
LIKE THAT.
WHEN I WAS AROUND SIX TO 10
YEARS OF AGE AND I STARTED
WEARING BRACES ON MY LEGS.
WE NEVER THOUGHT ABOUT SURGERY
AND I NEVER WAS BIG ON THAT AND
I DIDN'T REALLY WANT TO DO IT.
I JUST FOUND OUT THAT THERE WERE
WAYS, OTHER WAYS I COULD
STRENGTHEN MYSELF WITHOUT
SURGERY AND I USED TO WEAR
ORTHOTICS ON MY LEGS.
I USED TO EXPERIENCE PAIN.
I COULD NOT SIT ON MY LEGS OR
SQUAT ON THE GROUND.
IT WOULD HURT REALLY BAD AND I
WAS NOT ABLE TO DO THAT AND
THROUGH STRENGTH TRAINING AND
PHYSICAL THERAPY, I CAN DO ALL
OF THOSE THINGS NOW WITHOUT ANY
PAIN.
I REALLY HAVE TO FOCUS ON
GETTING STRONGER ALSO FOR WHAT I
GET OLDER AND MY BONES GET
WEAKER.
SO I'M NOT LIKE UNABLE TO DO
ANYTHING.
SO, I NEVER THOUGHT -- I USED TO
EXPERIENCE A LOT OF PAIN BUT
Dr. NOEL AND THE TEAM, THEY
REALLY HELPED ME FIGURE OUT WHAT
I COULD DO TO FIX THINGS LIKE
THAT AND SO I WOULDN'T BE IN SO
MUCH PAIN ANYMORE.
YES, SO, I WOULD GO TWICE A WEEK
TO LSU.
THIS STUDY WAS, WE WOULD DO
STRENGTH TRAINING.
I THINK -- I REALLY LOVE A TEAM
THERE.
WE ALL BECAME A BIG FAMILY AND
IT WAS REALLY NILES TO SEE THAT
THERE WERE PEOPLE WHO KNEW WHAT
WAS GOING ON -- I MEAN I'VE GONE
TO PHYSICAL THERAPY ALL MY LIFE
BUT PEOPLE WHO WERE -- REALLY
KNEW WHAT WAS GOING ON AND THEY
FOCUSED ON THAT ONE ASPECT OF
WHAT WAS GOING ON WITH ME AND WE
DID STRENGTH TRAINING AND WE
WOULD DO PUSH UPS ON THIS THING
WHERE YOU WOULD USE YOUR LEGS
AND I WOULD BE TIMED WALKING AND
IT WAS A CHALLENGE.
YOU CAN'T RUN BUT YOU HAVE TO
SEE.
IT WOULD SHOW ME HOW MUCH I'VE
GROWN OVER THE WEEKS, SEEING IF
I COULD MAKE IT TO THIS MARK.
THIS WEEK AND IF I DIDN'T MAKE
IT TO THAT MARK BEFORE.
AND WE WOULD RUN OBJECT A
TREADMILL AND PRACTICE STAMINA
WITH ME RUNNING.
NOT FALLING OVER EASIER, I
GUESS.
JUST LIKE GETTING MY STRENGTH UP
AND SHOWING ME LIKE IF YOU
THOUGHT YOU COULDN'T DO THIS
WELL YOU CAN, IT JUST TAKES
PRACTICE AND TIME.
BECAUSE IN PHYSICAL THERAPY WE
WOULD JUST DO THE SAME THING
EVERYDAY.
BUT WITH THIS STUDY, I WAS ABLE
TO BE EDUCATED AND ABLE TO
EDUCATE THEM, LIKE WHILE BEING
IN THEIR STUDY, I GUESS.
SO THAT WAS REALLY BIG AND I
LEARNED A LOT ABOUT IT.
I THOUGHT IT WAS JUST ME WHO HAD
IT AND I WAS JUST AN UNLUCKY
PERSON.
THERE'S NOT.
THERE'S A BUNCH OF PEOPLE WHO
HAVE IT.
I DID NOT KNOW NINE WAS MILD AND
SOME PEOPLE HAVE IT A LOT WORSE
THAN ME, I GUESS YOU COULD SAY.
I LEARNED THAT I COULD LIKE RUN
PRETTY WELL.
I HAD GOOD STAMINA.
I LEARNED THAT I COULD WORK ON
MY BALANCE A LOT.
THAT WOULD HELP ALSO.
>> I WAS REALLY STRONG IN MY
LEGS I JUST NEVER KNEW IT.
THEY REALLY HELPED ME FIND OUT A
LOT ABOUT MYSELF.
I LEARNED IF YOU RUN FOR TWO
MINUTES AND WALK 30 SECONDS IT
REALLY HELPS BUILDUP YOUR
STAMINA AND IT HELPED ME A LOT
WITH MY BALANCE.
I LEARNED THAT SITTING AND
STANDING IS NOT AS HARD AS I
THOUGHT IT WAS.
AND NOW THANKS TO THE STUDY AND
PHYSICAL THERAPY, I CAN DO THAT
WITHOUT A PROBLEM.
ALSO, GETTING OFF THE GROUND AND
MY BALANCE, THAT IS WAY EASIER
NOW.
I DON'T HAVE ANY SORT OF
PROBLEMS WITH THAT.
I FEEL LIKE THE BENEFITS OF THE
STUDY, THEY'VE STUCK WITH ME.
I DIDN'T JUST LOSE THEM.
BUT I ALSO THINK THAT IS PART OF
THE FACT I WAS ABLE TO BRING THE
SKILLS I LEARNED IN PHYSICAL
THERAPY AND SO I CAN DO THIS NOW
AND I CAN BUILD ON TOP OF THIS.
I WAS ALWAYS LIKE OH, NO, I'M
NOT GOING TO DO THAT.
NOW I'M LIKE, LET ME DO IT, I
CAN DO IT.
IT'S NOT REALLY -- THINGS I USED
TO BE NERVOUS ABOUT LIKE RUNNING
OR WALKING UP THE STAIRS, I CAN
DO THAT WITHOUT A PROBLEM NOW.
AND IT JUST MADE ME REALIZE,
LIKE, I NEED TO STOP HOLDING
MYSELF BACK FROM BRINGS AND I
NEED TO TRY AND EXPERIENCE NEW
THINGS.
I THINK THAT IT IMPROVED MY
RELATIONSHIPS WITH MY FAMILY,
BECAUSE THEY ALWAYS WOULD BE
LIKE HOLD YOURSELF BACK AND I'M
LIKE IT'S FINE, I'M NOT GOING TO
DO THAT AND I CAN'T DO THAT.
BUT MY MOM WAS VERY PROUD OF ME
THAT I PARTICIPATED IN IT
BECAUSE, YOU KNOW, I WAS LIKE, A
PRE-TEEN I DID NOT WANT TO DO
SOMETHING LIKE THAT.
I THINK IT IMPROVED MY
RELATIONSHIP WITH MY FAMILY.
THEY WERE PROUD OF ME.
I THINK WHETHER I DID IT OR NOT,
THEY WOULD BE PROUD OF ME.
JUST KNOWING THAT I WAS LIKABLE
TO TRY SOMETHING NEW AND I
LEARNED SO MUCH ABOUT MYSELF
THAT I WAS ABLE TO TEACH THEM AS
WELL.
THAT REALLY HELPED.
I THINK THEY DID A GREAT JOB
WITH MAKING IT APPEALING TO ME
AND THEY ALWAYS HAD A NEW TOPIC
TO TALK ABOUT.
I REMEMBER THE TEEN, THE GUY A
THAT I MAINLY WORKED WITH, HE
WOULD ALWAYS TALK ABOUT HIS PUGS
AND HIS FAMILY AND IT WAS REALLY
FUNNY AND LIKE, WE WOULD ALWAYS
WATCH MOVIES WHILE DOING STUFF.
I HAD TO LIKE WORKOUT WHILE
WATCHING MOVIES AND THEN IF I
WASN'T DOING IT OR IF I GOT
CAUGHT UP, I WOULD PAUSE THE
MOVIE AND BE LIKE YOU NEED TO DO
THIS.
Dr. NOEL HAS SUCH A BIG HEART.
IT WAS REALLY NICE WORKING WITH
HER AND HER BEING -- BOTH OF
THEM BEING SO EDUCATED ON WHAT
WAS GOING ON.
WHAT I WOULD TELL TO LIKE
ANOTHER PRE-TEEN THAT MIGHT BE
DOING THIS STUDY, YOU HAVE TO
THINK ABOUT THE LITTLE KIDS AND
THE FAMILIES WHO HAVE NO IDEAS
WHAT IS WRONG WITH THEIR CHILD
AND HOW MUCH YOU COULD EDUCATE
THEM ON THAT AND HOW MUCH YOU
COULD HELP THEM IN THE FUTURE.
BECAUSE YOU WERE HELPED, SO YOU
COULD ALSO HELP THEM.
I THINK THE BEST THING IS
REALIZING HOW MANY FAMILIES I
HELPED AND HOW MANY KIDS I
HELPED REALIZE HOW THEY CAN
STRENGTHEN THEIR SELVES AND BE
LIKE OH LIKE YOU CAN DO THIS.
YOU DO NOT HAVE TO HOLD YOURSELF
BACK.
AND ALSO, LEARNING STUFF, NEW
THINGS ABOUT MYSELF.
IT WAS REALLY EXCITING.
I DIDN'T KNOW THAT LIKE YOU
COULD USE LIKE WEIGHTS OR I
DIDN'T THINK MY LEGS COULD
HANDLE THAT AND I HAD ALWAYS
JUST EXERCISED.
I DIDN'T REALLY DO ANYTHING LIKE
THAT DIFFICULT AND IT WAS REALLY
HARD WHEN I FIRST STARTED OUT
BUT LIKE, YOU KNOW, NOW I CAN DO
THINGS LIKE THAT EASIER, I
GUESS.
I LOVE THE STUDY BUT I THINK
ABOUT HARDEST PART WAS THAT, I
REALLY STRUGGLED WITH SOMETHING
ELSE.
I WOULD STRUGGLE WITH SOMETHING
IF Dr. NOEL WOULD SAY FINE
TAKE A BREAK AND SHE WOULD BE
LIKE NOW WE'LL PUT MORE ON TOP
OF THAT AND CAN YOU DO THIS.
I ALWAYS DID IT.
THEY WEREN'T PUSHING ME TO MY
LIMIT.
IT WAS JUST LIKE, PLEASE,
LIKE -- I HAVE AMAZING FRIENDS.
I HANGOUT WITH MY FRIENDS LIKE
ALL SUMMER AND SCHOOL YEAR.
SO, THEY KNEW WHAT I WAS DOING.
THEY CAN DO THEIR PLANS WITHOUT
ME, I'M OK WITH THAT.
IT'S WORTH IT IN THE END.
I DIDN'T REALLY MISS OUT ON
ANYTHING.
I DIDN'T MISS OUT ON SLEEPOVERS
OR HANGOUT IN GENERAL.
MY FRIENDS COULD WAIT UNTIL I
WAS DONE WITH WHAT I HAD TO DO
TO HANGOUT WITH THEM.
I THINK I WOULD LOVE TO BE A
PART OF LIKE A FOLLOW-UP STUDY
TO SEE HOW I HAVE CARRIED ON
WITH WHAT THEY SHOWED ME HOW TO
DO.
I THINK THAT WOULD BE A REALLY
COOL EXPERIENCE AND I THINK IT
WOULD HELP MYSELF BUT ALSO A LOT
OF OTHER PEOPLE.
AND IN THE FUTURE, I THINK I
WOULD LOVE TO BE A PART OF ANY
STUDY THAT INVOLVES CEREBRAL
PALSY.
I THINK I WOULD ALSO REALLY LIKE
TO WORK ALONGSIDE SOMEONE ELSE
WHO HAS IT AND SEEING HOW WELL
WE CAN HELP EACH OTHER ALONG
WITH THE DISTRICTORS HELPING US
AS WELL.
I WOULD LOVE TO BE A PART OF
ANOTHER STUDY EVEN IF IT'S ON A
DIFFERENT TOPIC.
I WOULD REALLY LIKE THAT. I
THINK I WOULD WANT THEM TO KNOW
THAT THEY'RE HELPING A LOT OF
FAMILIES INCLUDING MINE.
AND THAT THEY'VE GATHERED A LOT
OF REALLY GOOD RESEARCH AND
THEY'RE STILL GATHERING MORE AND
I THINK IT'S REALLY EXCITING HOW
THEY HAVE LIKE FACES LIKE MINE
AND PEOPLE LIKE ME WITH CEREBRAL
PALSY WHO HAVE IT FIRSTHAND.
EDUCATING THEM AND EDUCATING
FAMILIES WITH KIDS WHO MIGHT
HAVE IT ON WHAT IT IS.
I THINK THE RESEARCH THAT THEY
HAVE ON IT IS REALLY GOOD.
SO, FUTURE RESEARCH THAT I WOULD
WANT TO SEE IS MAYBE LIKE MORE
STRENGTH TRAINING THAN I'VE DONE
BEFORE AND I THINK THAT WOULD BE
REALLY COOL TO SEE AND I LIKE
SEEING PROGRESS AND I THINK IT
COULD ALSO LIKE UP LIFT FAMILIES
SEEING MY PROGRESS AND OTHER
KIDS' PROGRESS THAT THEY'VE
GOTTEN FROM THIS STUDY.
SO I WOULD WANT TO DO MORE
STRENGTH TRAINING AND SEEING HOW
WELL I'VE GROWN.
WHEN I GROW UP, I WANT TO BE A
SPOKESPERSON ABOUT CEREBRAL
PALSY ACTUALLY.
I'M NOT JUST SAYING THAT.
I THINK IT WOULD BE REALLY DOOL
SEE LIKE ME WHO ARE HAS IT, WHO
HAS IT, DO RESEARCH ON IT AND
SHARING MY STORY WITH KIDS AND
BEING LIKE THERE IS A LIGHT AT
THE END OF THE TUNNEL.
THIS DUDOES NOT DEFINE YOU OR IO
BE A LAWYER.
>> GOOD MORNING, I'M JIM KOENIG.
I'LL BE MODERATING THE REST OF E
DAY.
THANK YOU TO CAYDANCE FOR
SHARING HER EXPERIENCES AS A
PERSON WITH CEREBRAL PALSY AND
AS A SUBJECT IN AN NIH-FUNDED
CLINICAL RESEARCH EFFORT.
HER PERSPECTIVESES ARE VERY
IMPORTANT IN HELPING TO FRAME
THE CRITICAL ISSUES FACING
PERSONS WITH CEREBRAL PALSY.
ALSO I WANT TO THANK RACHEL
BYRNE FOR SHARING THE
INFORMATION ABOUT CPS EARLY
DETECTION NETWORK AND THIS IS A
CRITICALLY IMPORTANT ELEMENT IN
UNDERSTANDING AND GETTING MORE
CP IMPLEMENTATION RESEARCH
ACTUAL LOW DONE AND I WANT TO
THANK HER FOR SHARING THE
EFFORTS THAT CPF IS UNDERTAKING.
AS YOU HEARD, THE PURPOSE OF THE
WORKSHOP IS TO PROVIDE AN UPDATE
ON CURRENT RESEARCH IN CEREBRAL
PALSY AND HOW IT RELATES TO THE
STRATEGIC PLAN FOR CP RESEARCH
THAT WAS PUBLISHED IN 2017.
WE WILL CONTINUE THIS MORNING BY
HEARING A SERIES OF SIX
PRESENTATIONS THAT WILL SPEAK TO
THE PROGRESS OF RESEARCH IN
BASIC AND TRANSLATIONAL
RESEARCH.
I WANT TO REMIND YOU, THAT THERE
ARE FORMING THEMES IN THE
STRATEGIC PLAN FOR BASIC AND
TRANSLATIONAL RESEARCH AND THOSE
THEMES ARE TO ENHANCE
UNDERSTANDING OF THE FUNDAMENTAL
MECHANISMS OF THE DEVELOPING
BRAIN, SPINE AND MUSCLE ACCESS
SO INTEGRATE STATE OF THE ART
NEUROIMAGING, TO CLARIFY
MECHANISMS AND ESTABLISH BOY
BIOMARKERS AND UNDERSTAND AND
UTILIZE NEURO PLASTICITY.
THE PRESENTATIONS THAT WORE
GOING TO HEAR OVER THE NEXT TWO
DAYS, ACTUALLY REPRESENTS
SNAPSHOTS OF SOME VERY EXCITING
SCIENTIFIC ADVANCES THAT HAVE
BEEN MADE SINCE 2017.
SO, TO START WITH THIS MORNING,
WE'LL BE HEARING A PRESENTATION
BY Dr. BHOOMA AVARMUTHAN AND
HER PRESENTATIONS IS TITLED
NEONATAL BRAIN INJURY IMPACTS ON
DEVELOPMENT.
AND A TALK BY MICHAEL KRUER.
HE IS AN ASSOCIATE PROFESSOR AT
UNIVERSITY OF ARIZONA SCHOOL OF
MEDICINE IN PHOENIX.
HIS TITLE WILL BE GENOMIC
INSIGHTS INTO THE NEUROBIOLOGY
OF CEREBRAL PALSY.
AND OUR NEXT SPEAKER WILL BE
Dr. NEHAL PARIKH.
A PROFESSOR AND DIRECTOR OF THE
CENTER FOR THE PREVENTION AND
NEURO DEVELOPMENTAL DISORDERS AT
CINCINNATI CHILDREN'S HOSPITAL.
HIS PRESENTATION IS TITLED EARLY
DIAGNOSIS OF PERINATAL BRAIN
INJURY DELAYED BRAIN DEVELOPMENT
AND CEREBRAL PALSY.
I'M SURE THESE PRESENTATIONS
WILL STIMULATE MANY QUESTIONS
AND I WILL WANT TO REMIND YOU TO
TYPE YOUR QUESTIONS UNDER THE
Q&A TAB AT THE BOTTOM OF THE
SCREEN.
IF YOU ARE WATCHING ON THE NIH
VIDEO CAST, PLEASE TYPE YOUR
QUESTIONS INTO THE LIVE FEEDBACK
BUTTON.
THE SPEAKERS WILL ANSWER YOUR
QUESTIONS DURING THE DISCUSSION
PERIOD.
SO WITH THAT, LET'S GO AHEAD AND
GET STARTED.
>> HI, MY NAME BHOOMA AND I'M AN
ASSISTANT PROFESSOR OF NEUROLOGY
IN ST. LOUIS MISSOURI AND I'VE
BEEN ASKED TO TALK ABOUT OUR
WORK ON NEONATAL BRAIN INJURY
IMPACTS ON DEVELOPMENT.
I HAVE NO RELEVANT DISCLOSURES
BUT MY COMPREHENSIVE DISCLOSURES
ARE HERE.
WE'RE HERE TO TALK ABOUT CP
WHICH IS A LIFELONG MOTOR
DISABILITY DUE TO A NON
PROGRESSIVE DISTURBANCE IN THE
DEVELOPING FETAL OR INFANT BRAIN
AND WHEN I THINK ABOUT MODELING
CP OR MODELING NEONATAL BRAIN
INJURY IN MICE, I THINK ABOUT
THESE ASPECTS OF THE DEFINITION,
WHAT DO WE MEAN WHEN WE SAY
NON-PROGRESSIVE DISTURB ANKERS
FETAL OR INFANT BRAIN AND HOW DO
WE CHARACTER USE THE MOTOR
MANIFESTATIONS IN THE MODELS
THAT WE CREATE?
AND WHEN I THINK ABOUT THIS
TITLE, AND THIS IS QUITE A BROAD
TITLE, SO I'M GOING TO TELL YOU
HOW I CONCEPTUALIZE THIS IN OUR
LAB, WHEN YOU THINK ABOUT WHAT
MEET OWE NATAL MEANS, THERE ARE
DEFINITIONS IN PEOPLE BUT TO
TRANSLATE THIS TO MICE IS AN
INTERESTING CONCEPT IS THAT IS
AN AREA OF CONTROVERSY.
THAT'S IMPORTANT TO DISCUSS AND
THINK ABOUT WHEN MODELING THIS.
WHEN WE TALK ABOUT BRAIN INJURY,
WHAT DO WE MEAN?
THERE ARE MULTIPLE DIFFERENT
TYPES.
ARE WE TALKING ABOUT FOCAL,
GLOBAL, SYSTEMIC?
AND THEN WHEN WE TALK ABOUT
DEVELOPMENT AND THERE ARE MANY
WAYS TO THINK ABOUT IT.
WE CAN THICK ABOUT IT IN A MICRO
SENSE.
WHAT IS HAPPENING TO BRAIN
STRUCTURE, WHAT IS HAPPENING ON
A MOLECULAR OR PATHOLOGIC LEVEL
BUT WE CAN ALSO THINK ABOUT IT
IN THE CONTEXT OF THE DEFINITION
OF CP, WHAT DO WE MEAN BY MOTOR
DEVELOPMENT, AND HOW DO WE
CHARACTERIZE THAT TO MAKE SURE
THAT THE MODELS WE DEVELOP ARE
CLINICALLY RELEVANT AND ARE
ALLOWING US TO ASK CLINICALLY
RELEVANT QUESTIONS.
IN OUR LAB, WE FOCUS ON HOW WE
CHARACTERIZE THE CLINICALLY
RELEVANT MOOD OR MAN MESSTATIONS
OF MODEL OF NEONATAL BRAIN
INJURIES.
THINKING ABOUT THE NEONATAL
ASPECT AND THIS IS SOMETHING
THAT MANY OF US IN THE ZOOM ROOM
RIGHT NOW FACE, MOUSE
GESTATIONAL TIMELINE IS VERY
DIFFERENT FROM THE HUMAN
GESTATIONAL TIMELINE AND WE TEND
TO THINK, BASED ON A FEW
MARKERS, BRAIN SIZE, DEGREE OF
MYELINATION THAT MOUSE POST
NATAL DAY 10, IS THE
APPROXIMATION FOR HUMAN TERM
GESTATION.
WE CALL THAT TERM EQUIVALENT
GESTATION IN MICE.
SO THAT REALLY BEGS TO QUESTION
WHAT DO WE MEAN BY PRO TERM OR
PREMATURE IN MICE BECAUSE WE
KNOW THAT MICE BORN AT MOUSE DAY
ZERO, THAT IS NOT PRE TERM FOR
THEM.
EVEN THOUGH THE BRAIN
DEVELOPMENT STAGE IS PRE TERM
WHEN YOU THINK ABOUT IT IN
HUMANS.
SO, IF WE COMPOUND A MOUSE POST
NATAL DAY 4, IS THAT THE BEST
APPROXIMATION OF PRO MATURITY
AND BRAIN INJURY THAT WE SEE
CLINICALLY?
SHOULD WE ALSO FOCUS ON TRYING
TO DEVELOP TRUE PRE-TERM BIRTH
MODELS IN MICE AND WHAT ARE THE
MANIFESTATIONS OF INJURIES THAT
WE SEE THERE?
THIS IS PARTICULARLY IMPORTANT
WHEN WE THINK ABOUT THE CP AND
WE KNOW IT'S HETERONENOUS AND
PEOPLE WHO HAVE AN ACQUIRED
BRAIN INJURY.
THE TYPE OF BRAIN INJURY YOU
HAVE REALLY DIFFERS DEPENDING ON
WHO YOU ARE AND WH WHERE YOU LID
THIS IS PUT INTO STRIKING RELIEF
WITH BEAUTIFUL EPIDEMIOLOGY DEEM
LOGIC STUDIES ACROSS THE GLOBE.
A LARGE PORTION OF PEOPLE WITH
CP ARE BORN PREMATURE AND HAVE
PREMATURE TEE ASSOCIATED BRAIN
INJURIES IN HIGH-INCOME
COUNTRIES LIKE IN THE COUNTRIES
IN NORTH AMERICA.
BUT, IF WE LOOK AT LOW AND
MIDDLE INCOME COUNTRIES AND THE
CP EPIDEMIOLOGY THERE, THE
PREPORTIONS SHIFT.
SEW FEWER, A SMALLER PERCENTAGE
ARE BORN PREMATURE IN BANGLADESH
AND SMALL NER GHAND AND IT
INCREASES SO WHEN WE THINK ABOUT
CP, IT'S IMPORTANT TO THINK
ABOUT ALL OF THESE IDEOLOGIES
AND NOT JUST ONE.
THIS WAS BROUGHT INTO -- THIS IS
A KEY POINT IN THIS BEAUTIFUL
PAPER THAT CELEBRATES 40 YEARS,
40 PLUS YEARS WE HAVE OF THE
CLASSIC AND REALLY GROUND
BREAKING VANNUCCI MODEL OF THE
MOUSE.
INTERESTINGLY, EPIDEMIOLOGY AT
THIS LEVEL OF SEVERE INSULT,
WHICH ESTABLISHED A LEVEL OF
VARIABILITY IN THIS MODEL, THIS
IS BEEN BOTH A BENEFIT AND A
CURSE TO MANY OF THE
INVESTIGATORS WHO HAVE USED IT.
AND WE SEE VARIABILITY ACROSS
MODELS IN NEONATAL BRAIN INJURY.
I CHOSE TO BELIEVE IN THE
BENEFIT OF THIS VARIABILITY.
BECAUSE I THINK IT'S REALLY
CLINICALLY RELEVANT.
CP IS HETEROGONOUS AND THE FEET
OWE TYPES ARE TOO.
SO, I THINK IT'S IMPORTANT TO
EMBRACE THE VARIABILITIES OF
THESE MODELS AND FOR A LONG
TIME, WE'VE BEEN STRUGGLING WITH
CONFORMITY AND WE'RE DOING THAT
IN A FEW WAYS, SO, WE'VE LOOKED
AT DIFFERENT MODELS THAT WE
THINK REPRESENT DIFFERENT TYPES
OF CPETIOLOGIES.
WE HAVE GLOBAL HYPOXIA-ISCMIA
AND WE HAVE A MODEL OF PREMATURE
BIRTH WHERE WE INDUCE THE DAMN
TO DELIVER ABOUT 24 HOURS EARLY
AND THESE ARE C50 SALMON BLOCK
SIX MICE SO INSTEAD OF
DELIVERING AT E19.5 THEY DELIVER
AT E18-5 SO THAT IS A MODEL OF
EXTREME PREMATURE BIRTH IF WE
THINK ABOUT IT FROM THE HUMAN
TIMELINE.
BUT IT'S ALSO MODEL OF TRUE
PREMATURE BIRTH FOR MICE ON
THEIR OWN TIMELINE.
SO WE'VE STARTED CHARACTERIZING
THAT MODEL AND THERE'S THE
CLASSIC VANNUCCI MODEL THAT IS
MOST ALIGNED WITH TERM STROKE
AND WE'RE WORKING WITH IVH
MODELS AND THESE LAST TWO MODELS
WE'RE WORKING WITH COLLABORATORS
AT WASHU.
I WANT TO IMPRESSES THAT WE FEEL
IT'S EXTREMELY IMPORTANT THOUGH
CHARACTERIZE MOTOR FUNCTION AND
STUDY THE PATHOLOGY OF CP AND
DEVELOPMENTAL INJURIES ACROSS A
WIDE VARIETY OF INSULTS AND WE
FEEL IT BEST ALLOWS US TO
UNDERSTAND THE SPECTRUM OF
CONCERNS AND CP.
WHEN WE THINK ABOUT MOTOR
DEVELOPMENT, THERE ARE A COUPLE
OF WAYS WE CAN THINK ABOUT THAT
TOO.
SO, WE CAN THINK ABOUT IT IN
TERMS OF FUNCTION, THINGS LIKE
OPEN FIELD, A WIDE ARRAY OF
STANDARD GAIN ANALYSIS METRICS
AND WE CAN ALSO THINK ABOUT IT
IN TERMS OF PHENOTYPE.
BASED ON OUR LABS' INTEREST WE
FOCUS ON ONE PHENOTYPE WHICH IS
DIS TONIA AND FOR THE REST OF
THE TALK, I'LL TALK ABOUT HOW WE
CHARACTERIZE DIS TONIA IN THESE
TOP TWO MODELS HERE THAT WE'VE
DEVELOPED IN THE LAB.
YOU CONTRACT MUSCLES YOU DON'T
WANT WHEN YOU MOVE A DIFFERENT
PART OF YOUR BODY.
AS I SAY THAT, YOU CAN PROBABLY
UNDERSTAND HOW FUNCTIONALLY
DOUGH BILL TATING DYSTONIA IS
AND IT'S A VERY COMMON PROBLEM
IN PEOPLE WITH CP.
IT IS CITED AS THE SECOND MOST
COMMON CAUSE OF PAIN IN PEOPLE
WITH CP.
IT'S ASSOCIATED WITH GREATER
GROSS MOTOR FUNCTIONAL
IMPAIRMENT.
IT IS PRETTY DIFFICULT TO TREAT
AND THAT'S BECAUSE TREATMENTS
TARGETED FOR DYSTONIA ARE
LIMITED AND ALSO THERE'S
EMERGING DATA THE EARLIER YOU
TREAT DYSTONIA THE BETTER.
BUT THERE'S A DELAY IN HOW OFTEN
WE'RE IDENTIFYING DYSTONIA IN
YOUNG CHILDREN, PRECLUDING THIS
POTENTIAL TREATMENT BENEFIT.
AND DESPITE THESE GAPS, DYSTONIA
IS COMMON.
SO, DYSTONIA IS THE MOST COMMON
FORM OF TONE IN 15% OF PEOPLE
WITH CP, AND IT'S THE MOST
PREDOMINANT FORM OF TONE.
BUT IT CAN BE PRESENT AND
SOMEWHERE UP TO 75% TO 80% OF
PEOPLE WITH CP AND JUST BY
UNDERSTANDING THE DEFINITION OF
IT, THE CHANCES OF IT BEING
FUNCTIONALLY LIMITING IN AWFUL
THESE PEOPLE, IS QUITE HIGH.
SO, THIS BEGS TO QUESTION, HOW
DO WE FOCUS ON H ON IT AND HOW E
DEVELOP TREATMENTS FOR DYSTONIA
AND HOW DO WE UNDERSTAND HOW
DYSTONIA DEVELOPS AFTER NEONATAL
BRAIN INJURY SO WE CAN BETTER
UNDERSTAND HOW TO TREAT IT WITH
PEOPLE WITH CP AND THIS IS OUR
MISSION IN THE LAB.
WE FIRST STARTED LOOKING AT
DYSTONIA IN OUR MODEL OF
FINANCIAL HIGH POXY HE IS
ESCHEMIA SO THESE ARE MICE THAT
ARE EXPOSED TO ROOM AIR AND THEN
HAVE THAT ROOM AIR DECREASED
OVER TIME AND THESE MICE GO
PULSE LESS AT ABOUT SIX MINUTES
AND THEN HAVE SOME MAINTAIN EKG
ACTIVITY SO THEY UNDERGO PULSE
LESS ARREST AROUND SIX MINUTES
AND MAINTAIN THAT FOR SIX
MINUTES THROUGH THE END OF THE
INSULT AND WE SEE SOME LIMITED
FUNCTIONAL IMPAIRMENT BASED ON
CLASSIC STUDIES IN THESE MICE.
SO, WE LOOKED AT SOME BASIC GATE
METRICS, STRIDE LENGTH, TRIED
DURATION AND SPEED.
YOU SEE THAT SPEED AND STRIDE
DURATION IS UNEFFECTED AND THE
BLUE IS HYPOXIA AND THESE ARE
MICE AT P28 AFTER INSULT OF P10.
YOU SEE THAT STRIDE LENGTH IS
SHORTER IN THESE MICE.
BUT THAT THE OTHER METRICS ARE
NOT DIFFERENT.
AND YOU ALSO SEE THAT THE ROT OR
FOLLOW IS NOT DIFFERENT IN THESE
MICE SO VERY LIMITED IN TERMS OF
FUNCTION IMPACT BUT DETECTABLE
FUNCTIONAL IMPACT.
THIS IS SOMETHING THAT IS
VALUABLE TO NOTE BUT DOES NOT
NECESSARILY LIMIT THE UTILITY OF
THE MODEL TO STUDY PHENOTYPES.
AND I'LL TALK ABOUT HOW WE DO
THAT SPECIFICALLY FOR DYSTONIA.
WE HAVE LOOKED AT EMG IN A
COUPLE OF DIFFERENT WAYS AS
POTENTIAL ELECTRIC PHYSICAL OWE
LOGICAL AND A MOUSE RUNNING WITH
AN IMPLANTED EMG ARRAY IN BOTH
THE GAS STOP AND THE INTERIOR
BILATERALLY SO THE CALVES AND
THE SHIN MUSCLE.
YOU SEE IN THE MOUSE THESE
MUSCLES CONTRACT AS THEY SHOULD
SO THEY'RE MICE THAT HAVE NOT
UNDERGONE HYPOXIA.
THE CON TRACTION ALTERNATE.
YOU SHOULDN'T HAVE YOUR SHINS
AND THE MUSCLE ON YOUR SHIN AND
THE MUSCLE IN YOUR CALF CONTRACT
AT THE SAME TIME.
THEY SHOULD ALTERNATE.
IN THE MICE AFTER HYPOXIA
THERE'S OFFER LAP.
IF WE DO A TIME TRIGGER AVERAGE
OF THESE SIGNALS OR ACROSS, YOU
CAN SEE THAT AT ZERO LAG BETWEEN
THESE SIGNALS, THAT'S THE ZERO
HERE, THAT THE MICE AFTER
HYPOXIA HAVE A SLIGHTLY HIGHER
AMP ATTITUDE MEANING THERE'S CO
CON TRACTION HERE AND THESE
HIGHER AMP ATTITUDES, THIS
VOLUNTEERING MOVEMENT TRIGGERED
OVERFLOW ACTIVATION OF THESE
MUSCLE, ARE BY DEFINITION A
POTENTIAL INDICATE OF DYSTONIA
AND WE DON'T SEE A DIFFERENT
BETWEEN THE SHAM EXPOSED AND THE
HYPOXIA EXPOSED MICE.
THIS IS 18 DAYS AFTER THE
INITIAL HIGH POX' EXPOSURE.
WOULD SEE THIS IN THE MODEL OF
THE BRAIN INJURY WE STUDY.
THERE'S A DELAY IN ONSET OF
DYSTONIA.
AND THIS DOES RECAPITULATE THE
CLINICAL DELAY WE SEE.
MONTHS AND SOMETIMES YEARS AFTER
THE BRAIN INJURY BEFORE DYSTONIA
DEVELOPS AND WE SEE IT IN THESE
MODELS AS WELL.
WHEN WE LOOK AT THE HYSTE
PATHOLOGY IN THESE MODELS WE
FOCUS ON STRIATAL INTER NEURONS
AND THE REASON IS BECAUSE OF
THEIR CLEAR IMPORTANCE IN
REGULATING MOVEMENT AND ALSO
BECAUSE AS A LAB, WE'RE
PARTICULARLY INTERESTED IN
NEURONS AND I'LL GET INTO WHY
SHORTLY.
WE SEE THAT IN THE HIGH POX'
EXPOSED ANIMALS THERE'S A
INCREASE IN THE NEURONS AND YOU
CAN SEE THAT JUST VISUALLY IN
THESE SLICES.
THAT'S A SIGNIFICANT DIFFERENCE
BETWEEN THESE GROUPS.
BUT IF WE LOOK AT ANOTHER TYPE
OF STRIATAL INTER NEURONS, YOU
SEE THAT THAT DIFFERENCE IS NOT
THERE SO THIS SEEMS TO BE
SPECIFIC TO HYPOXIA AND
SPECIFICALLY IN THE MODEL.
AND THAT'S INTERESTING TO US
BECAUSE WE KNOW IN OTHER MODELS
GENETIC DYSTONIA THERE'S
ABNORMAL INTER NEURONS SO WE'RE
GOING ON TO EXPLOIT THIS IN THE
LAB USING THIS RELATIVELY SUBTLE
PATHOLOGIC FINDING AND I WILL
NOTE THAT THERE'S NOT A
SIGNIFICANT DIFFERENCE IN ROY
SIZE AND THE ENGLI REGION SIZE O
CYSTIC LESIONS IN THIS MODEL AND
IT'S REALLY A SPECIFIC TARGETED
NEURON NUMBER OF DIFFERENCE AND
THAT REALLY ALLOWS US TO
MANIPULATE THE CIRCUITRY ALMOST
TO SOME DEGREE UNBOTHERED BY
SIGNIFICANT TISSUE INJURY THAT
MIGHT OTHERWISE EFFECT OUR
RESULTS SO WE'RE USING
TECHNIQUES RIGHT NOW TO
CHRONICALLY MANIPULATE INTER
NEURONS AND THIS AND OTHER
MODELS OF BRAIN INJURY TO SEE IF
THAT HELPS TURN UP OR TURN DOWN
THE DYSTONIA MARKERS THAT WE SEE
IN THESE ANIMALS.
AND I WANT TO TALK A LITTLE BIT
ABOUT HOW DYSTONIA IS
CHARACTERIZED IN MICE.
I SHOWED YOU THIS EMG
CHARACTERIZATION BUT DYSTONIA IS
NOTED TO BE CLASPING AND IT'S
DONE THAT SORT OF CLASPING IS
CHARACTERIZED IN THIS SPECIFIC
TASK, THIS TALE SUSPENSION TASK
WHERE MICE ARE FORCED TO
MAINTAIN A CERTAIN POSTURE AND
THEY END UP BEHIND LIMBS YOU CAN
SEE IN THIS GENETIC MODEL OF
DYSTONIA.
DYT1 WITH PICTURES FOR THIS
MODEL TAKEN FROM SAM AND BILL'S
LAB AT UT SOUTHWESTERN.
THE ISSUES WITH CLASPING HAS
BEEN LONG KNOWN TO THE FIELD.
IT'S ALL OR NOTHING THAT DOESN'T
ALLOW FOR A NUANCE DETECTION OF
DYSTONIA WITHIN A MOUSE.
OTHER THAN HOW OFTEN OR HOW MUCH
THEY CLASP.
THE OTHER IS THAT MANY GENETIC
MODEL OF DYSTONIA THAT
RECAPITULATE THE CLINICAL
MUTATIONS DON'T CLASP.
IT'S POSSIBLE THIS MAY BE ONE
MANIFESTATION OF DYSTONIA IN
MICE.
BUT A RANGE OF MILDER DYSTONIA
PHENOTYPES MAY NOT BE CAPTURED
BY LOOKING AT JUST CLASPING
ALONE.
AND PERHAPS FOR ME, AS A
PHYSICIAN SCIENTIST, THAT CURES
FOR PEOPLE WITH CP, MANY OF WHOM
DOES HAVE DYSTONIA, THE MOST
IMPORTANT THING TO ME IS THAT
PEOPLE DON'T CLASP.
YOU DON'T SEE A PERSON WITH CP
AND DYSTONIA COME IN AND DO THIS
AS AN EXAMPLE OF THEIR DIS TONE
Y THINKING ABOUT THE CLINICALLY
RELEVANT MARKERS OF DYSTONIA IN
MICE BECAME A REAL IMPORTANT
ISSUE FOR US IN THE LAB.
THE WAY WE TRIED TO DETERMINE
THAT WAS GOING BACK TO THE
CLINIC AND TRYING TO UNDERSTAND
WHAT THE EXPERTS SIDE OF THE
FEATURES OF DYSTONIA
SPECIFICALLY IN PEOPLE WITH CP
AND THEN TO TRY AND DEVELOP
QUANTITIVE METRICS OF THAT SO WE
LOOKED AT THE VIDEOS OF PEOPLE,
WE LABELED THE VIDEOS AND
LOOKING AT THE CERTAIN JOINTS WE
WERE ABLE TO LABEL AND WE USED
THOSE MARKERS TO DEVELOP
QUANTIFIABLE MEASURES OF THESE
QUALITATIVE EXPERTS SIDED
FEATURES AND ALL WITH THE
ULTIMATE GOAL OF TRANSLATING
THESE METRICS DIRECTLY TO MICE.
WHEN WE DID THIS IN PEOPLE, WE
FOUND A COUPLE OF METRICS THAT
TRACKED QUITE NICELY WITH
QUALITATIVE EXPERT RATINGS FOR
DYSTONIA AND ON THE X AXIS HERE,
SER SEW NO DYSTONIA AND EIGHT
MORE SEVERE AND SAME THING ON
THIS SIDE AND ON THE Y AXIS
HERE, THIS IS THE VARIABILITY OF
HOW CLOSE THE KNEES ARE TOGETHER
WHEN SOMEONE IS WALKING SO HOW
VARIABLE THE ABDUCTION IS OF THE
LEGS DURING GATE AND HERE ON THE
Y AXIS, IT'S FOOT ANGLE MINIMUM
SO THIS IS HOW CLOSE TO THE FEET
DO THE TOES COME TOGETHER AT ANY
POINT DURING GATE.
AND THESE METRICS WERE TIGHTLY
CORRELATED TO EXPERT QUALITATIVE
SEVERITY RANKINGS.
SO ABDUCTION VARIABILITY IN THE
LEGS AND ABDUCTION AMP ATTITUDED
WE SAW THIS ACROSS 1600
INDIVIDUALS WITH CP.
WE CHOSE TO APPLY THESE
TECHNIQUES TO LOOKING AT WHAT
HAPPENS IN OUR MICE AND I WILL
REMIND YOU THAT THIS IS WHAT A
MOUSE, A DY IT 1 MOUSE MOLDED
LOOKS LIKE A CONTROL MOUSE AND
HERE IS ONE OF OUR MICE THAT HAS
UNDERGONE THE HYPOXIC INSULT I
DESCRIBED.
A VERSION OF THAT INSULT AND
HERE IS A MOUSE BORN PREMATURE
AND THESE MICE ARE BOTH AT P35.
IF WE LOOKED AT VIDEOS OF HOW
THESE MICE MOVE, CONTROL ON THE
LEFT, HYPOXIA IN THE MIDDLE.
PREMATURE' ON THIS SIDE, THEY
ALL MOVE VERY DIFFERENTLY.
YOU SEE THAT THE CONTROL ANIMAL
HAS ITS LEGS AND THE HIGH POX
IAN MALL HAS THE LEGS MORE
STIFF, BROUGHT TO THE MID LINE
AND THIS ANIMAL THAT IS
EXPERIENCING PREMATURITY HAS ITS
LEGS STIFF AND OUT AND ABDUCTED.
NONE OF THESE ANIMALS LOOK
ALIKE.
NONE OF THEM ARE CLASPING BUT
YOU CAN SEE THAT BOTH ANIMALS
THAT HAS EXPERIENCED HYPOXIA AND
THE ANIMAL BORN PREMATURE, IT'S
HOLDING ITS HIND LIMBS MORE AB
DUCK TIVE.
WE CAN USE THE SAME TECHNIQUES
THAT WE CAN QUANTIFY LEG
ABDUCTION IN PEOPLE.
WE SEE IT ACROSS GROUPS HERE,
CONTROL VERSUS HYPOXIA AND
CONTROL VERSUS THE MICE BORN
PREMATURE AND THIS IS CORRECTED
AGE NOTING THAT THESE PREMATURE
MICE WERE BORN A DAY EARLY AND
THEY WERE ASSESSED A DAY LATER
THAN EVERYONE ELSE AND THESE ARE
THE GENETIC MODELS SO THESE ARE
THE MICE THAT ARE MODELS OF
DYT1.
ACROSS ALL OF THESE MICE, EVEN
THE MICE THAT CLASP, YOU SEE
THAT ABDUCTION IS THERE.
ANY TYPE OF INJURY ASSOCIATED
WITH WHAT MIGHT VISUALLY APPEAR
TO BE DYSTONIA IS ASSOCIATED
WITH THIS INCREASED ABDUCTION WE
FOUND TO BE A CLINICALLY
RELEVANT MARKER OF DYSTONIA IN
PEOPLE.
WE CAN LOOK AT THAT SAME MARKER
IN GATE.
THIS IS A CLEAR TREADMILL THAT
WE DEVELOPED IN THE LAB TO BE
ABLE TO QUANTIFY GATE METRICS
AND IF WE USE THIS TREADMILL
MARKER WE CAN LOOK AT ABDUCTION
OF THE LIMB TO MID LINE THROUGH
THE CLEAR BELT AND AGAIN USING
THE SAME TECHNIQUES, WE SEE THAT
MICE AFTER HYPOXIA AND ARE
PREMATURE TEE DATA FOURTH
COMING, WE SEE THE MICE AFTER
HYPOXIA DEVELOP AN ABDUCTION OF
THEIR LEGS FOLLOWING THE HYPOXIA
THAT THE CONTROLS DON'T EXIST.
WE BELIEVE THAT THINKING ABOUT
CLINICALLY RELEVANT MOTOR
DEVELOPMENT FEATURES IN MOUSE
MODELS OF BRAIN INJURY THAT ALSO
ARE CLINICALLY RELEVANT, AND IN
THAT SENSE, THEY HAVE TO BE
HETEROGENOUS AND CAPTURE CP
INSULTS THAT BOTH OF THOSE
TECHNIQUES TOGETHER, WE'RE
HOPING TO LEVERAGE THAT TO TRULY
GET A FULL UNDERSTANDING OF THE
CLINICALLY RELEVANT PATHO
PHYSIOLOGY THAT'S IMPORTANT FOR
US TO UNDERSTAND ABOUT CP.
SO, WE TALKED TODAY ABOUT
NEONATAL BRAIN INJURY, WHAT WE
MEAN BY MICE AND WHAT WE MEAN BY
BRAIN INJURY.
AND I MADE AN ARGUMENT FOR THE
VALUE IN BEHAVIORALIST AND AS A
MOVEMENT DISORDER PHYSICIAN
SCIENTIST, THINKING ABOUT MOTOR
DEVELOPMENT.
AND THINKING ABOUT HOW OUR
MODELS OF NEONATAL BRAIN INJURY
DON'T JUST RECAPITULATE SOME
FUNCTIONAL IMPAIRMENT BUT HOW
THEY REKA PIT TAUGHT LATE THE
MOTOR IN CLINIC AND IN OUR
FAMILIES.
I'D LIKE TO THANK EVERYBODY
INVOLVED IN THIS WORK
PARTICULARLY THIS GROUP OF
TRAINEES, ESTHER AND CAT.
WHO HAVE DONE THE PAINSTAKING
WORK OF COLLECTING A LOT OF THIS
DATA.
AND MY FUNDING SOURCES.
THANK YOU.
>> HELLO, MIME MICHAEL KRUER
JOINING YOU FROM PHOENIX,
ARIZONA TO TALK ABOUT GENOMIC
INSIGHTS INTO CEREBRAL PALSY.
MY THANKS TO THE ORGANIZERS FOR
THE OPPORTUNITY TO SHARE THIS
WORK WITH ALL OF US.
IT'S HARD TO BELIEVE BUT IT'S
BEEN OVER A YEAR AND A HALF
SINCE THE PUBLICATION OF OUR
WORLDWIDE EFFORT THAT LED TO
THIS PAPER BEING PUBLISHED IN
NATURE GENETICS.
THIS PROJECT WAS LED BY THREE
POSTDOCS, SARAH LEWIS, SOMAYEH
AND PETER JIN.
AND ASSISTANT PROFESSOR AT
WASHINGTON UNIVERSITY.
THIS PAPER SHOWED FOR THE FIRST
TIME STATISTICAL AND FUNCTIONAL
EVIDENCE THAT GENETIC MUTATIONS
CAN RESULT IN CP.
FURTHERMORE, SINCE THAT TIME,
THERE HAVE BEEN A NUMBER OF
IMPORTANT FOLLOW UPS STUDIES
THAT HAVE BEEN PUBLISHED.
COP OBJECT RATING AND EXTENDING
THE FINDINGS OF THE GENETICS
PAPER.
THIS POINT IN TIME I THINK IT'S
CLEAR THAT FOR SOME INDIVIDUALS
WITH CEREBRAL PALSY, THE CAUSE
OF THE SYMPTOMS IS GENETIC.
ONE POTENTIAL CRITICISM OF THIS
WORK THOUGH IS THIS REALLY
CEREBRAL PALSY?
AND IN RESPONSE, I WOULD SAY
THAT FUNDAMENTALLY CEREBRAL
PALSY IS A CLINICAL DIAGNOSIS.
ITS DEFINITION IS REALLY
INDEPENDENT OF IDEOLOGY.
OTHER MAJOR DISABILITIES, AUTISM
AND EPILEPSIES ARE AGNOSTIC TO
ETIOLOGY AS WELL.
IT'S DIFFICULT TO DISTINGUISH
CASES OF GENETIC CP FROM CASES
OF CP THAT MIGHT BE DUE TO MORE
CONVENTIONAL RISK FACTORS LIKE
PREMATURITY OR HIGHIA ESCHEMIC.
AND IF YOU LOOK AT THE PANEL ON
THE RIGHT YOU WILL SEE AN MRI
MONTAGE HIGHLIGHTING INJURY
PATTERNS AND INCLUDING POTENTIAL
ISCHEMIC INJURY AND ALL OF WHICH
COULD BE COMPATIBLE WITH THE CP
DIAGNOSIS AND SEEING IN
INDIVIDUALS WITH CP AND QUITE
INTERESTINGLY, ALL OF THESE
INDIVIDUALS AS IT TURNS OUT HAVE
MUTATIONS IN A SINGLE GENE
CALLED 4A1.
POTENTIALLY CHALLENGING SOME OF
OUR CLINICALLY HELD NOTIONS
ABOUT CP CAUSALITY.
IT MAY BE TIME FOR A DATA
APPROACH WHEN IT COMES TO CP.
MOST OF THE FORMS OF CP WE'VE
IDENTIFIED TO DATE HAVE
REPRESENTED LOW-HANGING FRUIT
AND THESE ARE SINGLE GENE
DISORDERS.
CONDITIONS WHERE A MUTATION IN A
SINGLE GENE IS ENOUGH TO TIP THE
SCALES FROM HEALTH TO DISEASE
AND SUCH MUTATIONS ARE OF
RELATIVELY LARGE EFFECT SIZE.
HOWEVER, MORE COMPLEX GENETIC
MECHANISMS CONTRIBUTE TO CP AS
WELL ALTHOUGH AT THIS POINT IN
TIME, THEY'VE REMAINED A BLACK
BOX.
THERE MIGHT BE SOME EXCITING
OPPORTUNITIES TO LOOK AT COMPLEX
FEATURES SUCH AS GENE-BY-GENE
AND GENE BY ENVIRONMENTAL
INTERACTIONS IN THE FUTURE.
LATER IN THE WORKSHOP WE'LL HEAR
ABOUT STAKEHOLDER ENGAGEMENT AND
TIN INCLUDES FAMILIAR LOWS AND
CLINICIANS.
FOR EXAMPLE, OUR WORK CONDUCTED
BY MY CLINICAL RESEARCH TEAM
WOULD NOT BE POSSIBLE WITHOUT
THE COLLABORATION AND SUPPORT OF
THIS CEREBRAL PALSY RESEARCH
NETWORK.
WE'LL HEAR ABOUT THE CPRN LATER
BUT THIS IS A NATIONWIDE
COLLABORATIVE COMPRISED OF
CENTERS OF EXCELLENCE AND CP
CARE, TRYING TO ESTABLISH BOTH
STANDARDS FOR CP.
IN ADDITION, IT'S ALSO BEEN SAID
IT CAN TAKE UP TO 10 YEARS FOR
NEW KNOWLEDGE TO BE IMPLEMENTED
INTO PRACTICE AND PERHAPS MORE.
AND ON THIS NOTE, THIS PAPER,
LED BY BHOOMA, DEMONSTRATED THAT
A SERIES OF VINIERS NEVERTHELESS
LED TO CONSIDERABLE VARIABILITY
IN HOW THEY WOULD DIAGNOSE
CEREBRAL PALSY.
EVEN WHEN PRESENTED WITH THE
CONSENSUS DEFINITION.
MAJOR POINTS OF THIS AGREEMENT
INCLUDED HYPO TONIC PC AS WELL
AS GENETIC IDEOLOGY BUT THIS
ARGUES FOR THE IMPORTANCE OF ON
GOING DYING A LOG WITH
CLINICIANS IN THE FACE OF NEW
RESEARCH FINDINGS.
BEFORE WE GO TOO MUCH FURTHER,
IT'S IMPORTANT TO RECOGNIZE THAT
CEREBRAL PALSY GENE DISCOVERY
FUNDAMENTALLY REQUIRES A
TRANSLATIONAL APPROACH AND SO
EXCELLENCE IN BIO INFORMATICS
AND WE'RE FORTUNATE TO HAVE AN
EXCELLENT TEAM IN PHOENIX AND A
WONDERFUL COLLABORATION WITH OUR
COLLEAGUES AT WASHU.
BUT THIS REPRESENTS ONE SIDE OF
THE COIN AND IDENTIFYING
PRIORITY GENOMIC VARIANTS IS IT
SOMETIMES THE ONLY THE BEGINNING
AS POTENTIAL MUTATIONS NEED TO
BE CONFIRMED AND VALIDATED.
THIS VALIDATION CAN TAKE A
VARIETY OF FORMS INCLUDING
EXPERIMENTS IN CELL LINES WHERE
USING OMICS TECHNOLOGIES AND
POTENTIALLY RETURNING TO ASSESS
PROTEIN MODEL.
INCREASINGLY, ANIMAL MODEL MUCH
CP WHETHER THEY'RE FLY MODEL
WHICH YOU WILL HEAR MORE ABOUT
IN A FEW SLIDES, OR ZEBRAFISH
MODELS, SUCH AS THIS ONE THAT
WAS UNDERTAKEN IN COLLABORATION
WITH MICHAEL FAYHE AND JAN
KASLIN ARE TAKING LIGHT IN
MECHANISM DISEASE.
WHAT DID WE LEARN SO FAR?
MUTATIONS ARE ENRICHED IN CP AND
THIS IS IMPORTANT BECAUSE FOR
SOME TIME, WE'VE KNOWN THAT
PARTICULARLY IN THE UNITED
STATES, CP TENDS TO BE SPORADIC
OCCURRENCE.
DE NOVO MUTATIONS ARE COMMON IN
NEURO DISORDERS AND OCCUR WHEN A
GENETICALLY HEALTHY FATHER AND
HEALTHY MOTHER NEVERTHELESS,
HAVE AN EFFECTED CHILD.
WHO DE NOVO DEVELOPS.
WE HAVE IDENTIFIED KEY PATHWAYS
MANY CONTROL DEVELOPMENTAL KEN P
CONNECTIVITY AND THE
REPRESENTATION OF THE CYTO
SKELETON HAS BEEN IMPORTANT.
THIS IS A TIME LAPSED VIDEO OF A
NEURON IN CULTURE FROM TOBIAS
MYERS LAB.
YOU CAN SEE THAT AK TIN HAS BEEN
LABELED SO WAVES OF ACTIN COME
OUT FROM THE SOMA AND SOME OF
THESE WAVES OF FIZZLE OUT WHILE
OTHERS ACTUALLY DRIVE EXTENSION
IN ACTIVE FASHION.
ALTHOUGH FURTHER STUDIES WILL BE
NEEDED TO UNDER THE MECHANISMS
BETTER, NEVERTHELESS, IT'S
FASCINATING SOME OF THE
MUTATIONS THAT IN THE COHORTS
SEQUENCES THUS FAR ARE PREDICTED
TO EFFECT THESE FUNDAMENTAL
MECHANISMS ARE NEURON
DEVELOPMENT AND CONNECTIVITY.
FURTHERMORE, WE'VE RECOGNIZED
THAT THERE IS A SUBSTANTIAL
CLINICAL AND GENETIC OVERLAP
WITH OTHER NEURAL DEVELOPMENT
DISORDERS AND MANY OF THE SAME
GENES, ALTHOUGH NOT ALL, THAT
HAVE BEEN IMPLICATED HAVE BEEN
IN OTHER NEURAL DISORDERS.
IN ADDITION, WE'VE LEARNED WE
HAVE A LOT TO LEARN.
THERE ARE CURRENTLY THOUGHT TO
BE HUNDREDS OF CP GENES THAT
EXIST BUT MANY OF THESE STILL
AWAIT DISCOVERY.
AND THIS IS JUST THE
REPRESENTATIVE EXAMPLE OF SOME
OF THE GENE DISCOVERIES THAT OUR
GROUP HAS BEEN INVOLVED IN.
SOME STUDIES WE'VE LED AND SOME
WE'VE COLLABORATED ON BUT EACH
OF THESE REPRESENTED IN AN
IMPORTANT DISCOVERY IN IT'S OWN
RIGHT.
A NUMBER OF THINGS HAVE
SURPRISED US.
ONE OF THE THINGS THAT'S BEEN
FASCINATING TO LEARN IS HOW
VARIABLE NDD PRESENTATIONS CAN
BE.
SO FOR EXAMPLE, WE NOW HAVE
EVIDENCE THAT MUTATIONS IN THE
SAME GENE CAN SOMETIMES LEAD TO
CP AND SOMETIMES LEAD TO OTHER
NEURO DEVELOPMENTAL DISORDERS.
SOMETIMES CO OCCURRING AND
SOMETIMES IN ISOLATION.
WE ALSO HAVE NEW EVIDENCE THAT
MUTATIONS AND SOME OF THE SAME
GENES THAT CAN LEAD TO CP, CAN
ALSO LEAD TO ADULT ONSET OR
PROGRESSIVE PHENOTYPES AND A AN
EXCELLENT EXAMPLE IS FROM
MICHAEL'S GROUP WHICH THEY
SHOWED VARIANTS IN CHDA MOST
OFTEN ASSOCIATED WITH AUTISM CAN
ALSO BE ASSOCIATED WITH
PROGRESSIVE DYSTONIA IN CERTAIN
PATIENTS.
REALLY HIGHLIGHTING SOME OF THE
VARIABILITY THAT WE SEE IN
CLINICAL PRESENTATION.
FURTHERMORE, THIS IS ALSO
ILLUSTRATED IN THE EXAMPLE THAT
HEREDITARY SPASTIC PARAPLEGIC
WHERE WE'VE KNOWN MUTATIONS IN
THESE GENES CAN LEAD TO DOUGH
GENERATIVE AND PROGRESSIVE
PHENOTYPES.
THEY SUGGEST THAT MUTATION IN
SOME GENES CLASSICALLY
ASSOCIATED WITH HSP SUCH AS ATL1
WITH LEAD TO CEREBRAL PALSY
PHENOTYPES.
ANOTHER SURPRISE THAT'S BEEN
DESPITE THE BREADTH OF GENETIC
FINDINGS IN CEREBRAL PALSY, THEY
CAN PROMPT CHANGES IN
MANAGEMENT.
AND THIS IS AN ACTIVE PROJECT
THAT IS STILL UNDERWAY.
THERE'S AN INTERNATIONAL WORKING
GROUP OF CONTENT EXPERTS AND
CEREBRAL PALSY GENETICS THAT'S
INVOLVED.
WHAT THIS WORKING GROUP HAS
DONE, TO REVIEW PUBLISHED DATA
FROM CP GENETIC STUDIES CLINICAL
AND RESEARCH STUDIES.
IT HAS REVEALED SEVERAL HUNDRED
GENES POTENTIALLY INVOLVED IN
CEREBRAL PALSY.
IN FOLLOW-UP REVIEW, HAS SHOWN
THAT IN A SURPRISING PREPORTION
OF CASES, THE IDENTIFICATION OF
THE GENETIC MUTATION IN ITS
SPECIFIC GENE MAY ACTUALLY
PROMPT A CHANGE IN MANAGEMENT
AND AN OPPORTUNITY FOR PRECISION
MEDICINE.
THIS IS UNPUBLISHED DATA THAT
SHOWS THAT FOR 25% OF THE GENES
THAT ARE IDENTIFIED BY CEREBRAL
PALSY GENE SEC WEDNESDAYING THIS
EXPECTED TO PROMPT A CHANGE IN
CARE.
IN SOME CASES ALLOWING PATIENTS
TO AVOID COMPLICATION AND IN
OTHER CASES, PROMPTING ACTUAL
CHANGE THIS TREATMENT OR THE
APPLICATION OF A NEW TREATMENT.
THESE ARE EXCITING HOWEVER IT'S
IMPORTANT TO POINT OUT THE
CAVEATS AS WELL.
WE KNOW THAT 62% OF THESE
ACTIONABLE GENES ACTUALLY HAVE
WEAK EVIDENCE SUPPORTING THEM.
EVIDENCE CLASS D OR LOWER.
BEGGING TO QUESTION WHAT DO WE
DO?
WELL THERE'S BEEN AN INCREASED
EMPHASIS ON THE POSSIBLE UTILITY
OF STUDIES FOR NEURO
DEVELOPMENTAL DISORDERS,
PARTICULARLY GENETIC ONES.
AND IF CAREFULLY CONDUCTED, CAN
ACTUALLY OFFER THE OPPORTUNITY
FOR HIGH-LEVEL EVIDENCE AND
ESSENTIALLY THESE STUDIES USE
EACH PATIENT AS HIS OR HER OWN
CONTROL GOING THROUGH A SERIES
OF REPEATED MEASURES IN WHICH
QUANTITIVE DATA IS TAKEN AT FACE
LINE FOLLOWED BY A INTERVENTION
OR PLACEBO AND WITH AN
INTERVENTION AND SO ESSENTIALLY,
THE PATIENT'S RESPONSE TO THE
INTERCEPTIONS CAN BE ASSESSED.
ALTHOUGH WE'LL HAVE TO SEE WHERE
THE TRIALS WILL TAKE US, THIS
OFFERS EXCITING OPPORTUNITIES AS
EARLY INTERVENTION OVER TIME,
MAY BE BECOMING INCREASINGLY
MEDICAL AS WELL AS THERAPY
BASED.
IN ADDITION, SOME STUDIES OF
GENETIC FORMS OF CP ARE STARTING
TO TEACH US NEW THINGS ABOUT
NORMAL HUMAN BRAIN DEVELOPMENT.
AS AN EXAMPLE I'M GOING TO TELL
YOU ABOUT A COLLABORATIVE STUDY
WE'RE WORKING ON WITH ALEX
KENTSIS.
THE BRAIN IS A MOSAIC IS EACH
NEURON MAY HAVE A DIFFERENT
GENETIC MAKE UP THAN ITS
NEIGHBOR.
THIS IS INVOKED TO EXPLAIN SOME
CAUSES OF DISEASE, PARTICULARLY
NEUROLOGICAL DISORDERS THAT
EFFECT THE DEVELOPMENT SUCH AS
EPILEPSIES.
HOWEVER, THROUGH UNBIASED
SEQUENCING STUDIES, IN THIS
CASE, IN POPULATIONS WE
IDENTIFIED TWO FAMILIES EACH
AFFECTED BY CP AS WELL AS
INTELLECTUAL DISABILITY, AUTISM
AND EPILEPSIES AND EACH FAMILY
HAD TWO EFFECTED CHILDREN AND
EACH OF THE CHILDREN HARBORED A
LOSS OF FUNCTION IN MUTATION IN
PGBD5.
THESE WERE PREDICTED TO LEAD TO
COMPLETE GENOMIC KNOCK OUT OF
THE GENE.
ESSENTIALLY NO FUNCTIONING GENE
PRODUCT.
WHEN INTERESTINGLY, PGB5 IS A
TRANSPOSE ACE AND THIS IS DATA
FROM ALEX'S GROUP IN WHICH THEY
SHOWED IN A MOUSE MODEL THAT
PGBD5 IS NECESSARY FOR THE
CREATION OF SMALL DELETION IN
NEURONS AND MAY LEAD TO
STRUCTURAL VARIATIONS BEING
PRESENT IN THOSE NEURONS.
THIS BEGS AN INTERESTING
QUESTION -- WE KNOW THAT THE
MUTATION IN THE EFFECTED
PATIENTS ACTUALLY LEADS TO A
COMPLETE LOSS OF PGD B5.
SO WHY WOULD A GENE THAT CAUSE
GENOMIC INSTABILITY IN THIS CASE
BE IMPORTANT FOR NORMAL BRAIN
DEVELOPMENT?
WE DON'T HAVE THE COMPLETE
ANSWER.
BUT THE DATA WE HAVE SO FAR IS
QUITE INTERESTING.
WE KNOW FROM YEARS OF RESEARCH,
THAT DURING THE COUR COURSE OF
DEVELOPMENT DEVELOPMENT IN THE
HUMAN BRAIN AND OTHER HIGH
UKRAINIANS IT WAVES THE ARE
NORMAL AND WE KNOW THAT THESE
WAVES OCCUR DESIGNATED TIMES AND
THE REASONS FOR THESE WAVES OF
PROGRAMS CELL DEN HAS NOT BEEN
SO CLEAR.
THE DATA THAT WE HAVE SO FAR,
SUGGESTS THAT PGBD5 MAY ACTUALLY
MEDIATE SOME OF THE NORMAL
GENOMIC VARIABILITY IN ORDER TO
CREATE DIFFERENT CLONES OF
GENOMICS AND ESSENTIALLY,
ENSURING THAT A GENETIC LEVEL,
NEURONS SHOW A SUBSTANTIAL
AMOUNT OF VARIABILITY.
THE HYPOTHESIZED THAT THIS
VARIABILITY MAY ACTUALLY SET THE
STAGE FOR BRAIN MICRO EVOLUTION
AND ALLOW THAT NEURAL NETWORKS
THAT THE MOST APPROPRIATELY
MATCHED TO THE ENVIRONMENT'S
DEMANDS TO BE MAINTAINED, WHILE
THOSE NEURONS THAT HAVE LESS
EFFECTIVE GENOMES THAT ARE LESS
MATCHED TO THE NEEDS OF THE
ORGANISM, MAY BE PRUDENT.
SO THIS IS A FASCINATING AREA
THAT WILL REQUIRE FURTHER STUDY
IN ORDER TO GET TO THE BOTTOM OF
IT.
ADDITIONAL STUDIES BEING
CONDUCTED BY SARAH LEWIS IN MY
LAB ARE LOOKING AT SOME OF THE
FUNDAMENTAL PATHWAYS THAT LEAD
TO CP AND ASKING THE QUESTION
WHETHER THESE ARE CAUSE OR
CONSEQUENCE.
AND IN PARTICULAR, SER A HAS
BEEN INTRIGUED BY A PATHWAY
CALLED EIF2 ALPHA FORMATION AND
THIS PATHWAY SERVES AS AN
IMPORTANT MEDIATOR OF STRESS
RESPONSES.
SARAH WAS INTERESTED IN EAF WHEN
SHE FOUND THAT IN FLY MODELS, SO
THESE WERE GENETIC MODEL OF THE
GENES THAT WE'RE FINDING IN
HUMAN PATIENTS, THAT EIF2 ALPHA,
WAS INSISTENTLY INCREASED.
AND THIS INDICATED A CHRONIC
ACTIVATION OF THE INTEGRATED
STRESS RESPONSE A AXIS.
THE GENETIC ALLYION WAS LEANING
TO THIS AND THE QUESTION WAS
WHETHER THIS WAS CAUSE OR
CONSEQUENCE OF THE MOTOR
PHENOTYPES THAT SHE WAS SEEING.
SHE PERFORMED EXPERIMENTS AND
EITHER KNOCKED OUT THE PHOSPHO
TASE OR OVER PRESSED THE KINASE
AND INDEPENDENTLY INCREASING A
EIF2A-P.
SARAH WAS ABLE TO SHOW WITH
THESE STUDIES WAS LOCOMOTION WAS
DECREASED AND IMPAIRED SO
ESSENTIALLY, ANIMALS THAT HAVE
INCREASED EIF2A-P THIS IS
NECESSARY AND SUFFICIENT FOR
THEM TO HAVE A LOCATE OWE MOTOR
IMPAIRMENTS.
FURTHERMORE, ALTHOUGH THIS IS
STILL SOMETHING BEING ACTIVELY
STUDIED IN THE LAB, THE EFFECTED
ANIMALS ALSO EXHIBITED DIS
KINETIC MOVEMENTS AND THIS
SUGGESTED TO US THAT EI F2A, MAY
BE A IMPORTANT CONVERGING
PATHWAY FOR CEREBRAL PALSY.
SARAH LOOKED FURTHER AT THE
INTEGRATED STRESS RESPONSE
PATHWAY AND HER QUESTIONS FOCUS
AROUND GENE ENVIRONMENT
INTERACTIONS SO LOOKING AT A
PARTICULAR FLY MODEL, SHOWING
MUTATIONS IN THE A GAP 1 GENE,
WHAT SARAH WAS ABLE TO SHOW WAS
THAT MUTANT FLIES, HERE DEPICTED
IN YELLOW, HAVE INCREASED
PHOSPHORYLATION OF EIF2 ALPHA IN
SPABASELINE, HOWEVER, IF THOSE
ANIMALS ARE CHALLENGED WITH AN
ENVIRONMENTAL STRESSOR, IN THIS
CASE, STARVATION, THEY WERE
UNABLE TO RESPOND FURTHER TO A
SECOND HIT.
IN THE WAY THAT NORMAL CONTROLS
DID.
THIS WAS QUITE INTERESTING
BECAUSE THIS SUGGESTED THAT
THERE WAS A LIMIT TO THE AMOUNT
OF STREETS OR ISR ACTIVATION
THAT ANIMALS COULD EXHIBIT.
AND SO SARAH LOOKED IN FOLLOW-UP
STUDIES AT A CHALLENGE WHICH
INDUCES ER STRESS, QUITE
INTRIGUINGLY SHE FOUND THAT
MUTANT FLIES BEGAN HERE IN THE
YELLOW SHOWED INCREASED
MORTALITY WHEN CHALLENGED WITH
THIS PARTICULAR STRESSOR
DEMONSTRATING GENE BY
ENVIRONMENT INTERACTION.
WE DON'T KNOW HOW WIDESPREAD
THIS ACTIVATION OF EIF2A IS BUT
IT'S REPRESENTED AN INTRIGUED
MODEL FOR FACTORS THAT EFFECT
OUTCOME IN CEREBRAL PALSY.
SO FOLLOW-UP QUESTION IS WHAT DO
WE STILL NEED TO LEARN?
I THINK THAT THERE'S A GENERAL
RECOGNITION THAT WE HAVE A NEED
FOR DIVERSITY.
THIS IS SOMETHING THE NIH
RECOGNIZES IN THEIR CURRENT
PRIORITIES.
IN A RESEARCH CONTEXT, IN THE CP
CONTEXT, WE NEED LARGER COHORTS
FROM DIVERSE BACKGROUNDS
PARTICULARLY BECAUSE MOST OF THE
INDIVIDUALS THAT HAVE BEEN
SEQUENCED SO FAR HAVE BEEN OF
EUROPEAN ANCESTRY AND THESE ARE
SHOWN US THE DE NOVO MUTATIONS
ARE IMPORTANT FOR CEREBRAL PALSY
BIOLOGY BUT YET UNPUBLISHED DATA
FROM NORTH AFRICA AND MIDDLE
EASTERN AND SOUTH EACH ASIAN
POPULATIONS IS ALSO STARTING TO
DEMONSTRATE THAT RECESSIVE
MODELS OF INHERENT WITH
DIFFERENT GENES AND PATHWAYS
IDENTIFY TO THESE STUDIES WILL
PROVE TO BE IMPORTANT SUCH THAT
STUDIES LED TO THE PGBD5 STROLL
THAT IS DEVELOPING.
I THINK THERE'S AN AGREEMENT IN
THE FIELD THAT WE NEED MORE
COMPREHENSIVE VARIANT ANALYSIS
AND THIS WILL BE POSSIBLE IN
PART THROUGH THE APPLICATION OF
WHOLE GENOME SEQUENCING IN
ADDITION TO EXCELLENT SEQUENCING
WITH ANALYSIS OF NON CODING
REGIONS, COPY NUMBER VARIANTS,
STRUCTURAL VARIANTS, REPEAT
EXPANSIONS AND OTHER TYPES OF
VARIANTS THAT HAVE NOT YET BEEN
COMPREHENSIVELY ASSESSED IN CP.
THERE'S A NEED FOR ROBUST META
ANALYSIS OUTLINES.
POTENTIALLY USING APPROACHES
LIKE TATA THAT COMBINE MULTIPLE
MODES OF INHER TANTS AND A NEED
TO ATTRACT ADDITIONAL
COMPUTATIONAL BIOLOGY TALENT TO
THE FIELD.
WE HAVE A NEED FOR MORE COMPLEX
STUDY DESIGNS OVER TIME.
ALLOWING US TO LOOK AT POLYGENIC
CONTRIBUTIONS, GENE BY GENE
INTERACTIONS AND ALSO GENE
ENVIRONMENT INTERACTIONS.
FINALLY, WHERE DO WE GO FROM
HERE?
I THINK THERE'S A AGREEMENT ALSO
THAT THERE IS A HUGE NEED FOR
COLLABORATION AND COLLABORATIVE
NETWORKS.
WE'VE BEEN EXCITED BY THE
OPPORTUNITY TO DEVELOP AND
EMPLOY PARTICIPANT FACING TOOLS.
FOR EXAMPLE, WE'VE DEVELOPED AN
IOS-BASED I CONSENT APPLICATION
THAT IS FULLY SELF ENCLOSED AND
THIS ALLOWS POTENTIALLY
INTERESTED FAMILIES TO INTERACT
DIRECTLY WITH THE APP TO LEARN
MORE ABOUT OUR STUDIES AND TO
ENROLL THEMSELVES IF THEY'RE
INTERESTED.
WITHIN A COMPLETELY SELF
CONTAINED ELECTRONIC
ENVIRONMENT.
THIS WILL ALLOW US TO REACH MORE
FAMILIES AND ENGAGE MORE PEOPLE
IN THIS TYPE OF RESEARCH.
I THINK THERE'S CERTAINLY
EXCITING POSSIBILITIES FOR
PRECISION PHENOMICS AND A MULTI
DIMENSIONAL CHARACTERIZATION OF
CP AND FOR NEXT-GEN OUTCOMES
RESEARCH.
WE THINK THERE ARE OPPORTUNITIES
FOR CLINICAL DATA MINING AND
FROM ELECTRONIC MEDICAL RECORDS,
BUT ALSO INCLUDING NEUROIMAGING,
POTENTIALLY INCLUDING FACIAL
PHOTOS, PATIENT VIDEOS AND NEURO
PHYSIOLOGY TO DEFINE PATIENT
PHENOTYPES AND GENE PHENOTYPE
INTERACTIONS AND THERE'S A NEED
FOR RISK FACTORS ASSESSMENT.
I THINK AGAIN THERE ARE
TREMENDOUS OPPORTUNITIES FOR
THIS IN CP.
FINALLY I SHALL THERE'S AN
INCREASINGLY ROLE FOR TRIALS AND
IF PROPERLY DESIGNED AND
CONDUCTED, SUCH STUDIES CAN
PROVE TO BE VERY INFORMATIVE AS
WE LOOK FOR BETTER TREATMENTS
FOR GENETIC FORMS OF CP AND FOR
CP IN GENERAL.
SO WITH THAT I'LL CONCLUDE.
BUT I HAVE TO GIVE A HEARTY
THANKS TO MY AMAZING LAB.
OUR MANY FANTASTIC COLLABORATORS
AND SUPPORTING ORGANIZATIONS.
AND OF COURSE MY WONDERFUL
FAMILY.
WITHOUT WHOM I WOULD NOT BE
HERE.
THANK YOU, VERY MUCH.
>> GOOD AFTERNOON, MY NAME IS
NEHAL PARIKH AND TODAY I WILL
PRESENT EARLY DIAGNOSIS OF
PERINATAL BRAIN INJURY OR
DELAYED BRAIN MATURATION AND
PREDICTION OF CEREBRAL PALSY.
I HAVE NO CONFLICTS TO DISCLOSE.
I WILL TRY TO PRESENT THE MOST
COMMON BRAIN ABNORMALITIES AND
BRAIN PREDICTION OF CP.
WE'LL GO OVER ENHANCING
PROGNOSIS WITH ADVANCED MRI.
I WILL BRIEFLY DISCUSS THE ADDED
VALUE OF EARLY FUNCTIONAL
TESTING AT THREE TO FOUR MONTHS
CORRECTED AGE SUCH AS THE
NEUROLOGICAL EXAM AND THE
GENERAL MOVEMENT ASSESSMENT AND
WE'LL WRAP THINGS UP WITH
CONTINUED GAPS IN OUR NOM AND WE
CAN GO NEXT TO APPROVE EARLY
DIAGNOSIS AND PREDICTION OF CP.
THERE'S CONSENSUS THAT CP IS
CAUSED BY EARLY BRAIN INJURY OR
BRAIN MALL FORMATIONS.
HOWEVER, NEUROIMAGING IS NORMAL
UP TO 30% CASES OF CP.
WHY THAT BIG GAP IN DIAGNOSIS?
WELL, I BELIEVE THERE ARE THREE
KEY ADVANCEMENT THAT'S CAN HELP
CLOSE THAT GAP.
ONE IS TO ENABLE BETTER
UNDERSTANDING AND KNOWLEDGE OF
DIFFERENT TYPES OF PERINATAL
BRAIN INJURIES.
WE ALSO NEED TO TRANSITION FROM
SUBJECTIVE TO OBJECTIVE METHODS
TO DIAGNOSE INJURY AND IF WE
EMPLOY MORE SENSITIVE ADVANCED
MRI MODALITY SUCH AS FUNCTIONAL
MRI WE WILL CLOSE THAT GAP.
AND NEONATAL OR CIE, PRE TERM
INFANTS HAVE A COMBINATION OF
SEVERAL TYPES OF BRAIN INJURIES
AND BRAIN IMMATURE TEE THAT
RESULTS IN NEURO DEVELOPMENTAL
IMPAIRMENTS INCLUDING CP.
INCLUDING FOR HEMORRHAGE AND
LEUKOMALACIA BUT THANKS TO
ADVANCES IN NEO IN AAL CARE WE
HAVE REDUCED THESE COMMON
ABNORMALITIES AND WITH
INCREASING USE OF BRAIN MRI AT
TERM, WE'RE SEEING MORE SUBTLE
DIFFUSE INJURIES AND DELAYS THAT
MAY BE PREDICTORS OF CP.
DELAYS IN WHITE MATTER AND
CORTICAL GRAY MATTER MAT
YOU'MAT MATURATION ANDSO ARE WHD
THE
USE EXCESSIVE HIGH SIGNAL
INTENSITY ABNORMALITY AND MY
GROUPS CAUSED WHITE MATTER
ABNORMALITY WHEN WE CAN QUANTIFY
IT.
IN ONE STUDY WE DID 16% OF
BABIES BORN LESS THAN A THOUSAND
GRAMS OR EXTREMELY WILL HE BIRTH
WAY EXHIBITED MODERATE TO SEVERE
DELAYED MATURATION AND YOU SEE
IT HERE IN A PRE TERM INFANT
IMAGE AT 40 WEEKS YOU CAN SEE
THE GYRAL ARE UNDER DEVELOPED
AND SMOOTH AND COMPARED TO A PRE
TERM INFANT IMAGE AT 40 WEEKS
WHERE THERE ARE NO DELAYS IN THE
LOWER IMAGE WHERE YOU CAN SEE
MUCH MORE DETAILED AND DEEPER
CELL AND MORE GYRAY.
WE CAN USE AUTOMATE MODES AS
WELL.
AT LEAST USING SUBJECTIVE
ASSESSMENT IT WAS NOT PREDICTIVE
OF MOTOR DEVELOPMENT AND IT WAS
PREDICTIVE OF COGNITIVE
DEVELOPMENT.
WE EXAMINED THIS MORE OBJECTIVE
MEANS OF MEASUREMENT USING
AUTOMATED PIPELINE AND WE
STUDIED A REGIONAL COHORT OF 395
PRE TERM INFANTS BOTH IN
SOUTHWEST OHIO AND WE CALLED
THIS COHORT THE SYNAPSE COHORT
OR EARLY PREDICTION STUDY AND
THESE FOUR MEASURES INCLUDED
SURFACE AREA, GENERAL INDEX,
DEPTH AND INTER CORTICAL
CURVATURE AND UNFORTUNATELY NONE
OF THESE WERE PREDICT PREDICTIV.
THERE'S AN ASSOCIATION OF
COGNITION AND LANGUAGE
DEVELOPMENT BUT NOT WITH
CEREBRAL PALSY.
WHAT ABOUT WHITE MATTER LESIONS?
THESE ARE SEEN BETWEEN SEVEN TO
39% OF BABIES IN LARGE COHORTS.
YOU CAN SEE HERE ON T2 OR SORRY
T1 WEIGHTED IMAGING, THIS BRIGHT
SIGNAL ABNORMALITY THAT YOU CAN
SEE THERE IN A LINEAR FASHION
YOU CAN SEE ON IMAGES AND
THEY'RE ALL PERRY VENTRICULAR
AND THIS NICE FIGURE HERE WAS
LOOKING AT THE DISTRIBUTION OF
THESE LESIONS AND OVER 100
BABIES THAT WERE STUDIED OF
WHICH OVER 60 I BELIEVE HAD
LESIONS AND THE DISTRIBUTION
AGAIN IS VERY MUCH PEIR
VENTRICULAR AS CAN YOU SEE HERE
AT IMAGES AND ON THIS MAP YOU
CAN SEE THE BLUE ARE THE FINAL
TRACKS.
AND YOU CAN SEE HOW CLEARLY
THESE LESIONS LIE WITHIN THE
PATHWAY OF THE SENSORY MOTOR
TRACKS.
SO NO SURPRISE, THIS STUDY AT
LEAST FROM BRITISH COLUMBIA, DID
SEE A STRONG CORRELATION WITH
MOTOR ABNORMALITY AND ODDS RATIO
OF 29.8 AND A LARGE STUDY IN THE
U.K. OF PRE TERM INFANTS DID NOT
SEE AN ASSOCIATION.
SO THIS LESIONS ARE STILL SOME
ADDITIONAL WORK THAT NEEDS TO BE
DONE.
WHAT WE DID TO GET AT THIS TRUTH
WAS WE SEGMENT THESE LESIONS TO
GET A BETTER QUANTIFICATION
RATHER THAN A NUMBER OF LESIONS
WHICH IS WHAT OTHER INVESTIGATES
HAVE DONE.
WE SAID WE WOULD QUANTIFY THE
VOLUME OF THIS LESION.
AND WE WERE ABLE TO DO THIS WITH
A HIGH DEGREE OF RELIABILITY AND
WE DICHOTOMIZED THIS VALUE
BECAUSE IT'S NOT NORMALLY
DISTRIBUTED AND THOSE THAT HAD
SEVERE LESIONS DID HAVE AN
ELEVATED RISK OF EARLY DIAGNOSIS
OF CEREBRAL PALSY WITH AN ODDS
RATIO OF 3.5 SO THE LESIONS ARE
SEEN IN UP TO 30% OF PRE TERM
INFANTS ESPECIALLY WITH THE
ADVENT OF INCREASING USE OF TERM
MRI AND SEEING THIS MUCH MORE
READILY AND ULTRASOUND IS NOT
ALWAYS THE BEST TOOL TO USE IF U
ONLY INTER FON ENAL USE AND UP
TO 10% DEMONSTRATE SIGNIFICANCE
OF LESIONS MOST COMMONLY
HEMORRHAGES BUT ATROPHY IS ALSO
SEEN AS A RESULT OF THE
HEMORRHAGE.
AND THESE SIGNIFICANT LESIONS
ARE PREDICTIVE OF CEREBRAL
PALSY.
AT LEAST MODERN TO SEVERE
CEREBRAL PALSY IN SOME COHORTS
SUCH AS THE STUDY FROM HUGH SUSN
HUNDRED DOLLARS WHERE THEY SAW
THE RATIO OF 5.2 AND LOOKING AT
THE COHORT FROM U.K. AND DAVID
EDWARD'S GROUP THEY DID NOT SEE
ANY CORRELATION WITH CEREBRAL
PALSY.
ONE WAY TO IMPROVE OUR ABILITY
TO PREDICT CEREBRAL PALSY IS TO
COMBINE THESE DIFFERENT TYPES OF
INJURIES INTO A SINGLE SCORE, A
COMPOSITE SCORE OF BRAIN INJURY
AND MATURATION AND THIS SCORE
THAT THE DOCTORS PUT TOGETHER
ARE PREDICTED NOT ONLY OF TWO
OUTCOMES AND LONG-TERM NEURO
DEVELOPMENTAL OUTCOMES UP TO
SEVEN YEARS OF AGE.
AND THIS IS A COMPOSITE OF FOUR
DIFFERENT TYPES OF TISSUE,
CEREBELLUM, WHITE MATTER, GRAY
MATTER AND DEEP GRAY MATTER AND
BASICALLY THE CEREBELLUM SCORE
IS A SIGNIFICANT BUT WEAK
PREDICT OR OF MOTOR SCORES AT
SEVEN YEARS OF DAY, WE NEED MORE
ON CEREBELLAR LESIONS BUT IT'S
SOMETHING THAT IS WORTH LOOKING
AT MORE CLOSELY.
AS I MENTIONED, DIFFUSE
EXCESSIVE HIGH SIGNAL INTENSITY
ABNORMALITIES ARE OBSERVED MORE
COMMONLY THAN ANY OTHER LESIONS
AND UP TO 70% OF PRE TERM
INFANTS HERE WE HAVE IMAGED THE
42 WEEKS AND YOU CAN SEE IN THIS
VALUE THERE'S A BRIGHTER SIGNAL
THAT REPRESENTS DWMA AND IN THIS
CENTRAL WHITE MATTER AND IN THE
PERRY VENTRICULAR WHITE MATTER
ON THE RIGHT.
IT'S SUBJECTIVE AND SOME
RADIOLOGISTS MAY SAY THERE'S NO
DEHSI AND SOME MAY THERE'S NOT.
WE'VE BEEN WORK ON A SOFTWARE
FOR OVER A DECADE AID THAT HAS
BEEN COMPLETED AUTOMATED USING A
DEEP LEARNING ALGORITHM AND THE
SOFTWARE BELIEVES THE YELLOW ARE
MOST ABNORMAL AND QUANTIFIES
SEGMENTS AND QUANTIFIES AS DEHSI
OR DIFFUSE WHITE MATTER
ABNORMALITY AND ON THE RIGHT IS
A HEAT MAP OF DEHSI THAT THE
SOFTWARE QUANTIFIES AND
IDENTIFIES IN OVER 300 BABIES
AND YOU CAN SEE THE DISTRIBUTION
IS PRIMARILY PERIVENTRICULAR BUT
THERE'S A GOOD A LOT IN THE SUB
COURT CO WHITE MATTER.
IT'S SUBJECTIVE IN ITS
RELIABILITY AND RA RADIOLOGY
DIAGNOSIS IS POOR AND FAIR AT
BEST.
IT'S NOT ASSOCIATED WITH
CEREBRAL PALSY.
IN MULTIPLE STUDIES INCLUDING
TWO STUDIES THAT WE PUBLISHED.
HOWEVER, WHEN WE QUANTIFY IT,
IT'S PREDICTIVE OF CEREBRAL
PALSY WITH AN ODDS RATIO OF 31.6
AND PRO DICK TIVE OF DAILY
SCORES AT AGE 2 INCLUDING DAILY
MOTOR, COGNITIVE LANGUAGE SCORES
AND THIS FINDING ACTUALLY IS A
EXTERNAL VALIDATION OF A PRIOR
STUDY THAT WE DID FROM A
DIFFERENT COHORT THAT WE
PUBLISHED ALMOST 10 YEARS AGO.
SO, WHAT ABOUT DIFFUSION MRI I
MENTIONED THE NEED TO DO MORE
ADVANCED IMAGING TO IMPROVE THE
SENSITIVITY OF DETECTION OF
INJURIES.
ESPECIALLY AS THESE INJURIES
HAVE BECOME MORE SUBTLE AND
DIFFUSE.
SO WE LOOKED AT THE CINEPS
COHORT IN BABIES WHERE OBTAINING
MULTI-SHELL DATA WHERE WE GET
MULTIPLE DIRECTIONS UP TO 100
DIRECTIONS OF DIFFUSION DATA AND
THIS ALLOWS US TO MODEL THE
DIFFUSION OF WATER AND CREATE
THESE HIGHER ORDER DIFFUSION MRI
MODELS THAT CANNOT ONLY GET AT
MICRO STRUCTURE BUT ALSO MACRO
STRUCTURE OF WHITE MATTER
INTEGRITY AND WE LOOKED AT
SEVERAL SENSORY MOTOR TRACKS AND
THE MOST IMPORTANT ONCE ONCE, HE
YOU CAN SEE IN THIS IMAGE,
BILATERAL SUPERIOR RADIATIONS
THIS THE MOTOR COMPONENT AND C
IS THE SENSORY COMPONENT AND.
LEFT AND RIGHT.
AND THE YOU CAN SEE HERE VIEWS.
SO INTERESTINGLY, IN CHILDREN
THAT DEVELOP EARLY CP, ALL OF
THESE TRACKS WERE ABNORMALLY
DEVELOPED WHEN WE LOOKED AT BOTH
MACRO AND MICRO STRUCTURE.
THINGS SUCH AS FIBER CROSS
SECTION AND FIBER DENSITY AND WE
BELIEVE THAT THESE COULD BE USED
TO PREDICT CP.
THIS IS WAS ONLY AN ASSOCIATION
STUDY BUT WE HOPE TO ASSOCIATE
THIS WITH THE TRUE DIAGNOSIS OF
CP AT AGE 2.
WE DID ANOTHER STUDY IN THE
SYNAPSE COHORT USING DIFFUSION
IMAGE MODELING AND HERE WE
DEVELOPED A STRUCTURAL
CONNECTION TONE USING AND ALSO
CAME UP WITH RAV THEORY METRICS
TO UNDERSTAND BRAIN NETWORK
EFFICIENCY AND SEGREGATION AND
WE NOTED DECREASED SEGREGATION
IN THOSE INFANTS THAT WENT ON TO
DEVELOP EARLY CEREBRAL PALSY.
AND THE SEGREGATION WAS
DECREASED IN NUMEROUS CENTURY
MOTOR NODES THAT ARE SHOWN HERE
ALONG WITH ALSO NODES THAT SUB
SERVE CON NA TIVE FUNCTION WHICH
SHOULDN'T SURPRISE US BECAUSE WE
KNOW HALF OF THESE INFANTS WITH
CEREBRAL PALSY GO ON TO DEVELOP
COGNITIVE IMPAIRMENTS.
INTERESTINGLY, THERE ARE A FEW
STUDIES THAT CORRELATED
DIFFUSION MRI WITH PRE TERM
INFANTS BUT IT'S THE FEW STUDIES
THAT ARE OUT THERE ARE VERY
PROMISING AND MOST OF THEM ARE
ASSOCIATION STUDIES.
THE FEW THAT ARE PREDICTIVE,
SUGGEST A POSITIVE LIKELIHOOD
RATIO BETWEEN 2.8 AND
AND YOU CAN SEE THAT SOME OF THE
SAME TRACKS THAT ARE SHOWED IN
THE PRIOR IMAGE, SUCH AS THE
FINSPINAL TRACK AND THE RADIATIS
AND THE CORP IS ASSOCIATED WITH
A MOTOR SCORES.
SO, WHILE THESE STUDIES ARE
PROMISING, THERE ARE ALL SMALL
AND NONE OF THEM DID ANY KIND OF
INTERNAL OR EXTERNAL VALIDATION
BECAUSE IT'S DIFFICULT TO DO
INTERNAL VALIDATION WITH SMALLER
STUDIES.
THAT IS SOMETHING THAT NEEDS TO
BE DONE.
SO, WITH THIS SYNAPSE COHORT
WE'RE IN A GOOD POSITION TO DO
JUST THAT.
FIRST, WE DECIDED TO LOOK AT
STRUCTURE CONNECTIVITY
BIOMARKERS IN INFANTS WHERE WE
WERE ABLE TO SUCCESSFULLY GET
STRUCTURAL CONNECTOME AND HAVE
OUTCOME DATA FOR CEREBRAL PALSY.
14% OF OUR COHORT DEVELOPED CP
AND THIS INCLUDES GMF MILD CP
AND WE USED ELASTIC NET TO
IDENTIFY THE TOP BIOMARKERS.
AND AGAIN, HERE WE USED GRAPH
THEORY BIOMARKERS AND HERE, YOU
CAN SEE, THE SIX BIOMARKERS
INCLUDING THE STRENGTHS OF THE
SAGITTAL STRATUM AND PONTINE
CROSSING TRACT AND THEY ARE ALL
HEAVILY INVOLVED IN MOTOR
FUNCTION AND WE ALSO SAW THAT
LOCALLY EFFICIENCY OF THE
POSTERIOR CORONA RADIATA AND
CLUSTERING CO EFFICIENT OF
SAGITTAL EXTRA STRATUM WERE CP
AND COMBINED THEM THE AREA UNDER
THE CURVE WAS 0.80 AND YOU CAN
SEE THAT HERE IN THE AUC CURVE
ON THE UPPER RIGHT -HAND CORNER.
THIS IS A RESPECTABLE NUMBER AND
ESPECIALLY WHEN YOU CONSIDER
THAT THE BEST CLINICAL MODEL,
THAT INCLUDES CLINICAL
PREDICTERS SUCH AS DPD AND IVH,
IN ADDITION TO STRUCTURAL MRI,
THE BEST THAT WE CAN DO WAS AN
AUC AT .65.
AUC AT .8 IS INSUFFICIENT TO
MAKE INDIVIDUAL LEVEL
PREDICTIONS.
WHEN WE COMBINE THE STRUCTURAL
CONNECTIVITY BIOMARKERS WITH
EXISTING BIOMARKERS, WE STILL
DON'T GET MUCH BETTER THE AUC
WAS .81.
SO, WHAT IS IS IT THAT IS
PROHIBITING US FROM GETTING
THERE?
ESPECIALLY WHEN OTHER STUDIES
HAVE REPORTED AUCs AS HIGH AS
.9?
WELL, ONE THING IS THAT THOSE
STUDIES SUCH AS THE ONE FROM THE
NETWORK, INCLUDED DEATH AS ONE
OF THE OUTCOME MEASURES.
IT WAS CP OR DEATH AND THE OTHER
THING IS THEY USE MONITOR TO
SEVERE CP RATHER THAN INCLUDING
MILD CP.
I'LL GET INTO THAT IN A LITTLE
BIT.
HERE IS MORE DATA FROM OUR
SYNAPSE COHORT AS I MENTIONED,
14% OR 48 INFANTS IN TOTAL
DEVELOPED CP INCLUDING MILD CP
AT TWO YEARS CORRECTED AGE.
AND HERE ARE THE PROGNOSTIC
VALUES FOR THE DIFFERENT
MEASURES THAT WE'VE EXAMINED SO
FAR.
SO SEVERE INJURIES ON STRUCTURAL
MRI HAD A 29% SENSITIVITY AND A
90% SPECIFICITY SO THE
SENSITIVITY AGAIN IS QUITE LOW,
ESPECIALLY SINCE WE'VE INCLUDED
LEVEL 1 GROSS MOTOR FUNCTION
CLASSIFICATION AND CP AND THE
KEY THINGS AND QUITE LET FOR
MOST OF THESE TESTS AND GENERAL
MOVEMENT AND NEUROLOGICAL AND
EVEN WHEN YOU COMBINE IT WITH
STRUCTURAL MRI AND HAS BEEN
RECOMMENDED AND AND GUIDELINE
AND WE DON'T DO VERY WELL AS FAR
AS SENSITIVITY IS CONCERNED SO
IT'S DIFFICULT TO RULE OUT CP
AND THE SPECIFICITY IS HIGH AND
THE AUC AGAIN IS NOT IDEAL TO
WON'T RULE IN AND RULE OUT
CEREBRAL PALSY.
WHEN WE COMBINE GMA WITH
STRUCTURAL CONNECTIVITY AND MRI,
OUR AUC DOES NOT IMPROVE.
MUCH ABOVE THE .81 THAT I JUST
SHOWED UP.
SO, AGAIN, I THINK THAT THIS HAS
TO DO WITH THE FACT THAT WE'RE
INCLUDING THIS MILDER FORM OF CP
WHICH MANY PARENTS WOULD ARGUE
IS STILL IMPORTANT THAT WE FIND
A WAY TO DIAGNOSE THESE KIDS
EARLIER THAN TWO YEARS OF AGE.
SO, WHEN WE RESTRICT OUR
PREDICTION TO MODERATE TO SEVERE
CP OR THE GMSCS IS 2 OR HIGHER,
FIRST WE'RE LIMITED IN OUR
COHORT BECAUSE ONLY 3.6%
DEVELOPS CP.
THANKFULLY.
BUT IT DOES MAKE PROGNOSTICATION
DIFFICULT.
IN OUR CASE, THE AT LEAST FOR
STRUCTURAL MRI AND GMA, THOSE
ARE ONLY TWO PREDICTORS SO THAT
IS -- WE HAVE THE POWER TO DO
FIVE PREDICTORS WITH THIS
OUTCOME MEASURE AND THAT'S WHAT
WE DID AND SURE ENOUGH, THE
SENSITIVITY IMPROVES
SIGNIFICANTLY UP TO 83% WITH
STRUCTURAL MRI AND WHEN YOU
COMBINE IT THE SENSITIVITY GOES
DOWN BUT THE SPECIFICITY GOES UP
AND THE POSITIVE LIKELIHOOD
RATIO IS 187.
YOU NEED AT LEAST ABOUT 30 TO 35
TO MAKE INDIVIDUAL LEVEL
PROGRESS NOSTACATESES SO IT
PROGNOSTICATION SO TO CRUEL OUT
CP, YOU ARE GOING TO MISS ABOUT
18 TO 20% OF THE CASES AND WITH
CP OR UP TO 40 IF YOU ARE USING
STRUCTURAL MRI AND GMA SAYS
BECOMING THE STANDARD IN MANY
INSTITUTIONS INCLUDING OURS.
WHEN WE LOOK AT STRUCTURAL
CONNECTIVITY WE SEE AN AUC MUCH
THE SAME AS GMA AND STRUCTURAL
MRI.
AND KEEP IN MIND THIS IS THAT
DETERMINE CORRECTED AGE WHERE
THE GMA AND YOU HAVE TO WAIT
UNTIL THREE TO FOUR MONTHS TO
OBTAIN THOSE TESTS IN YOU WANTED
TO BE ACCURATE.
SO, WHEN YOU ADD GMA TO
STRUCTURAL CONNECTIVITY AND
STRUCTURAL MRI THE AUC REMAINS
HIGH.
THERE'S PROMISE HERE FOR
MODERATE TO SEVERE CP
PREDICTION, HOWEVER, MORE NEEDS
TO BE DONE FOR MILDER CP.
SO WHAT CAN WE CONCLUDE FROM
ADVANCES IN RESEARCH IN THIS
AREA?
WELL, ONE, I THINK WE CAN SAY
THAT BETTER KNOWLEDGE AND
OBJECTIVE ASSESSMENT OF
STRUCTURAL MRI INJURY, HAVE
CONTRIBUTED TIME PROVE
SENSITIVITY IN PREDICTING
CEREBRAL PALSY.
STRUCTURAL MRI PLUS GMA APPEARS
SUFFICIENTLY ACCURATE TO PRO
DICTIONARY MODERATE TO SEVERE
CP.
AT LEAST LEVEL 2 OR HIGHER.
HOWEVER, SENSITIVITY OF
STRUCTURAL MRI PLUS GMA OR HINE
ARE TOO LOW AND THIS COMBINATION
IS UNABLE TO RULE OUT ALL LEVELS
OF CP.
INCLUSIVE OF MILD CP.
WE NEED MORE SENSITIVE AND
OBJECTIVE TESTS TO RULE OUT MILD
CP.
AND GRAPH METRICS AND STRUCTURAL
CONNECTIVITY MAY BE POISE TO
FILL THIS KNOWLEDGE GAP AND
IMPROVE PREDICTION OF MILD CP AS
WELL.
OUR COHORT, WE'VE COLLECTED
RESTING STATE FUNCTIONAL
CONNECTIVITY DATA AND MR DATA AS
WELL AND WE BELIEVE THIS WILL
FURTHER ENHANCE SENSITIVITY
ESPECIALLY IN THE MILDER FORMS
OF CP AND GENETIC, EPI GENETIC
T. AND BIOMARKERS ALSO OFFER
ADDITIONAL MEANS TO ENHANCE
PREDICTION OF CP AND WE HAVE
SOME OF THIS DATA AS WELL AND
OTHERS, OTHER GROUPS ARE LOOKING
AT THIS SO IT WILL BE GREAT TO
SEE THESE STUDIES AS WELL AS A
COMBINATION OF THESE BIOMARKERS
BOTH IMAGING AND BLOOD
BIOMARKERS TO IMPROVE OUR
ABILITY TO SENSITIVITY DETECT CP
AND RULE IT OUT WHEN IT'S NOT
NEGATIVE.
WE ARE ALSO USING, WE AND OTHERS
ARE USING MACHINE AND DEEP
LEARNING APPROACHES TO
INDIVIDUAL EYES PREDIIZE THEPREE
WITH ALL OF THESE STUDIES THAT
ARE HOPEFULLY GOING TO FIND MORE
AND MORE BIOMARKERS WE WILL NEED
A LARGE NIH STUDY THAT WILL
OFFER EXTERNAL VALIDATION WHICH
IS CRITICAL BEFORE IT CAN BE
TRANSLATED TO THE BEDSIDE.
THANK YOU SO MUCH FOR YOUR
ATTENTION.
SO THANK YOU TO VERY MUCH TO
DrTHE DOCTORS.
WE'LL TAKE A SHORT BREAK AND
RECONVENE AT 1:15:00 P.M.
EASTERN TIME SO IN ABOUT 30
MINUTES. THANK YOU.
OUR NEXT SET OF PRESENTATIONS
WILL BEGIN WITH Dr. QUINLAN
WHO IS AN ASSISTANT PROFESSOR IN
THE GEORGE AND ANNE RYAN CENTER
FOR NEUROSCIENCE AT THE
UNIVERSITY OF RHODE ISLAND.
SHE WILL SPEAK ABOUT DEVELOPING
NEW BIOMARKERS AND
PHARMACEUTICAL TREATMENTS FOR
CEREBRAL PALSY.
FOLLOWING Dr. QUINLAN, WILL BE
A PRESENTATION FROM Dr.
NATALIE MAITRE NEURO DEVELOPMENT
AT HIGH-RISK NEW BORNS AND
REHABILITATION AT LONG-TERM DIS
BILL TEES.
NOW OWE DEVELOPMENT OF HIGH-RISK
NEWBORNS AND REHABILITATION OF
LONG-TERM DISABILITIES AT CP AND
OUR FINAL SPEAKER TODAY WILL BE
Dr. BURNADE BERNADETTE GILLICK M
THE UNIVERSITY WHICH.CORTICAL PY
FROM NEUROLOGICAL INSULT IN BOTH
ADULT AND PEDIATRIC POPULATIONS.
SO LET'S GO AHEAD AND GET THIS
NEXT SET OF PRESENTATIONS
STARTED.
>> HI, I'M AN ASSISTANT
PROFESSOR AT THE COLLEGE OF
PHARMACY AT THE UNIVERSITY OF
ROAD I'D LINE.
SIXTH I HAVE A BACKGROUND IN
SPINAL CORD PHYSIOLOGY.
SO I BRING THIS SKILLS SET TO
DEVELOPING NEW BIOMARKERS AND
PHARMACEUTICAL TREATMENTS FOR
CEREBRAL PALSY.
SO BIOMARKERS AS WE ALL KNOW, CP
IS NOT DIAGNOSED UNTIL ONE OR
TWO YEARS OF AGE, EVEN THOUGH
THERE ARE METHODS OF EARLY
PREDICTION.
AT AGE OF LESS THAN SIX MONTHS
IN KIDS.
SOME OF THE BEST METHODS FOR
EARLY DETECTION, ARE QUALITATIVE
ASSESSMENTS AND GENERAL
MOVEMENTS ASSESSMENT.
NEUROLOGICAL INFANT EXAM ALONG
WITH MRI.
WHAT IMPRESSESES ME MOST ABOUT
THIS LIST OF GOOD EARLY
PREDICTORS, IS THAT TWO OF THEM,
THE GENERAL MOVEMENT ASSESSMENT
AND THE NEUROLOGICAL EXAM ARE
BASED ON SPONTANEOUS MOVEMENTS
IN INFANTS AND REFLEX CIRCUITS
WHICH ARE PRESENT IN INFANTS.
SO THEY'RE REALLY MOVEMENT BASED
EXAMS.
AND THESE EXAMS WITH A TRAINED
AND QUALIFIED OBSERVER,
POTENTIALLY COULD BE EVEN MORE
ACCURATE THAN AN INACCESSIBLE
MRI, AT LEAST BASED ON THE DATA
PRESENT INSIDE THIS ARTICLE WHAT
IS IT THAT THE GENERAL MOVEMENTS
EXAM LOOKS AT AND WE'RE GOING TO
FOCUS IN ON THE GENERAL
MOVEMENTS ASSESSMENT.
IT LOOKS AT SPONTANEOUS MOVEMENT
IN INFANTS AND HERE IS MY
3-MONTH-OLD DAUGHTER MAKING SOME
VERY TYPICAL MOVEMENTS FOR AN
INFANT THAT AGE.
SO, WHAT IS SPONTANEOUS
MOVEMENTS.
NEWBORNS AND PRE TERM INFANTS
MAKE MOVEMENTS THAT CAN BE
CLASSIFIED AS RISING.
THEY'RE NOT KNOWN FOR
COORDINATED MOTOR ACTIVITIES OR
LOCOMOTION AND IT'S NOT UNTIL
SEVERAL MONTHS OF AGE, AROUND
SIX OR SEVEN MONTHS OF AGE THAT
THEY CAN MAKE INTENTIONAL
MOVEMENTS, THEY CAN PICK UP THAT
CHERRIO OR MAKE ANTI GRAVITY
MOVEMENTS SORRY WEIGHTS OR
CRAWL.
BRIDGES THESE TWO PATTERNS OF
MOVEMENT, IS A PERIOD KNOWN AS
THE FIDGETY MOVEMENT AND IT
SIGNALS THE TRANSITION FROM
SPINAL-DRIVEN LOCOMOTIVE
ACTIVITY TO CORTICAL
SPINAL-DRIVEN VOLUNTARY
INTENTIONAL MOVEMENTS.
SO, IN TYPICAL DEVELOPING KIDS,
THE FIDGET TEE MOVEMENTS IS
INCREDIBLY INDICATIVE OF THE
CORTICAL SPINAL TRACT TAKING
CONTROL.
IN KIDS WITH CEREBRAL PALSY,
MOVEMENTS INSTEAD OF BEING
FIDGETY, ARE CRAMPED AND
SYNCHRONIZED.
SO, LET'S TAKE A LOOK AT WHAT
PRODUCES THESE DIFFERENT
PATTERNS OF MOVEMENT FROM THE
PERSPECTIVE OF COURSE OF THE
SPINAL CORD PHYSICALLOLOGIST,
ME.
LOOKING AT WEEKS POST
CONSUMPTION IN HUMANS AND
FOCUSING ON THE TIME THAT
PRODUCES THE SPONTANEOUS RITHING
MOVEMENT AND THE START OF THE
SPONTANEOUS MOVEMENT AND ENDING
WITH THE TRANSITION O CORTICAL
CONTROL AND FIDGETY MOVEMENT.
THE FIRST THING WE NEED FOR
DEVELOPING NERVOUS SYSTEM TO
PRODUCE THESE SPONTANEOUS
MOVEMENT IS INTERVENTION OF THE
MUSCLE.
SO DEVELOPING MOTOR NEURONS,
EXIT THE NEURAL TUBE AND REACH
OUT INTO THE PERIPHERY AND THE
DEVELOPING MUSCLE.
NOW THAT HAPPENS EARLY IN
DEVELOPMENT BUT OBVIOUSLY, AND
AROUND THE SAME TIME THIS IS
HAPPENING, YOU HAVE FIBERS
WRITHING IN THE SPINAL CORD
ARRIVING FROM THE DEVELOPING
NUCLEUS IN THE BRAIN STEM AND
SEROTONIN IS VERY IMPORTANT IN
THE DEVELOPMENT FOR THE SPINAL
CORD SPECIFICALLY IN OTHER
NEURAL AREAS AS WELL.
SO SEROTONIN PROMOTES NURITE
OUTGROWTH AND THE DEVELOPMENT ON
THE CELLULAR LEVEL AND PROMOTES
NEURAL DEVELOPMENT AT THE
CIRCUIT LEVEL.
SO IT DEPOLARIZES AND
FACILITATES SPONTANEOUS NEURAL
ACTIVITY.
THE SPONTANEOUS NEURAL ACTIVITY
ISN'T DRIVEN BY SEROTONIN ALONE
BUT BY GLUTE MATE, GABA AND TO
SOME DEGREE AND IT'S PROMOTED BY
SEROTONIN.
SEROTONIN IS RELEASED BY VOLUME
TRANSMISSION SO THERE'S A LOT OF
IT JUST FLOATING AROUND IN THE
SPINAL FLUID AT THIS
DEVELOPMENTAL STAGE.
NEURONS, BY DEVELOPING, EX
EXPRESS SEROTONIN RECEPTORS
THROUGHOUT THE SOMA SO THEY'RE
NOT RESTRICTED TO SYNAPTIC SITES
BUT SENSITIVE TO SEROTONIN IN
THE DEVELOPMENTAL TIME PERIOD.
SO SEROTONIN, AS YOU CAN TELL,
IS ONE OF MY BIG INTERESTS IN
THE FORMING AND THE SHAPING OF
NEURAL ACTIVITY.
WHAT HAPPENS, OF COURSE, AFTER
SPONTANEOUS MOVEMENTS BEGIN,
THIS PROMOTES MORE DEVELOPMENT
IN THE CIRCUIT FORMATION SO YOU
HAVE THE MUSCLE THE MOTOR
NEURONS AND THEY'RE ALSO NEURONS
IN THE SPINAL CORD THAT
EVENTUALLY WILL HELP SEGREGATE
SENSORY ACTIVITY AND LEFT AND
RIGHT COORDINATION.
SO FORMATION OF THOSE CIRCUITS
IS VERY DEPENDENT ON THAT
SPONTANEOUS ACTIVITY.
AT 24 WEEKS POST CONCEPTION,
CORTICAL SPINAL TRACKS REACH
CERVICAL SPINAL CORD AND THIS IS
JUST THE ENTRY POINT INTO THE
MOST AREAS OF THE SPINAL CORD
AND THE PROGRESSION INTO THE
LUMBAR CORD AND THE PARTICULAR
FORMATION OF SYNAPSES, BY
CORTICAL SPINAL TRACKS, WILL
PROGRESS FOR THE NEXT FEW YEARS.
AND OF COURSE, AT THIS POINT,
POST NATALLY THE CORTICAL SPINAL
TRACT IS TRYING TO EXERT CONTROL
OVER THE SPINAL CORD.
WHAT HAPPENS IN BETWEEN THE
POINT WHERE THEY A ARRIVE AND
THE POINT WHERE THEY'RE TAKING
CONTROL?
THIS IS AN AREA THAT INTERESTS
ME VERY MUCH IN COMPARING THE
TYPICALLY DEVELOPING NERVOUS
SYSTEM WITH A NERVOUS SYSTEM
THAT HAS HAD AN INSULT OR AN
INJURY THAT WILL CAUSE CEREBRAL
PALSY.
ONE OF THE THINGS THAT HAPPENS
DURING THIS TIME IS AVENUER ANTS
HAVE THE CORTICAL SPINAL TRACK.
AND THEY ARE APPROPRIATE TO THE
PRO PLEA AT MOTOR NEWERRANCE
WILL REMAIN.
WITHOUT THIS, THERE'S THE
MAINTENANCE OF REFLEX RADIATION
AND THAT'S SOMETHING THAT WE
ACTUALLY SEE IN KIDS WITH CP IS
THAT THEY HAVE MORE REFLEX
RADIATION AND STRONGER REFLEX
ACTIVITIES THAN YOU WOULD EXPECT
IN A TYPICALLY DEVELOPING CHILD.
SO THE FACTS THAT THESE AVENUER
ENTERS ARE NOT PRUNED IS
INDICATIVE OF A WEAKENED
CORTICAL SPINAL TRACT THAT IS
NOT KICKOFF SOME OF THE
DEVELOPMENTAL MINE STONES.
>> THE GOALS ARE FOCUSING ON THE
SPINAL CORD AND AREAS THAT ARE
ALTERED DURING DEVELOPMENT IN
INDIVIDUALS AND MODEL ANIMAL
MADELS OF CP AND TO DEVELOP
BIOMARKERS AND TARGETS FOR
TREATMENT.
ULTIMATELY, MY GOAL IS TO FIND
PHARMACEUTICAL INTERCEPTIONS
THAT COULD REDUCE THE SEVERITY
OF MOTOR DYSFUNCTION AND I'M
USING ANIMAL MODELS, I HAVE TO
USE AN ANIMAL MODEL WITH
PROMINENT MOTOR DEFECTS TO
QUANTIFY THE EFFECTS AND THE
AMELIORATE I REMEMBA -- AND THEH
PEOPLE THAT HAVE CP SO I HAVE
COLLABORATORS WHO WORK WITH
PEOPLE, I EXCLUSIVELY WORK WITH
ANIMAL MODELS IN MY LAB.
SO LET'S TALK ABOUT ANIMAL
MODELS.
WHEN SOMEONE MENTIONS ANIMAL
MODELS IN A RESEARCH CONTEXT,
PROBABLY EVERYONE'S MIND GOES TO
RODENTS.
FOR A GOOD REASON.
RODENTS ARE GREAT ANIMAL MODELS
FOR MANY REASONS.
BUT THEY MAY NOT BE THE BEST
MODEL FOR CEREBRAL PALSY IN
LOOKING AT MOTOR DEFICITS.
AND THE REASON IS BECAUSE THE
RODENTS ARE POST NATAL BRAIN
DEVELOPERS SO IF YOU INFLICT AN
INJURY TO RECAPITULATE CEREBRAL
PALSY, MOST PEOPLE DO THAT ON
POST NATAL DAY 7 AND IT'S A WEEK
OF AGE POST NATALLY IS WHEN A
RODENT BRAIN RESEMBLES THE
DEVELOPMENTAL STAGE OF A PERRY
NATPERINATAL HUMAN.
THIS IS A GREAT MODEL TO LOOK AT
BUT IF YOU ARE LOOKING AT MOTOR
DEFICITS, MOST STUDIES DO EVEN
REPORT MO MOTOR DEFICITS AND THE
THAT DON'T REPORT DEFICITS
REPORT MILD DEFICITS.
THERE'S A LOSS OF GRIP STRENGTH,
THERE'S LOSS OF FINE MOTOR CON
DINNATIONS THAT I CAN'T RUN ON A
LADDER QUITE AS WELL.
I SLIP A FEW MORE TIMES.
THEY HAVE LESS TIME THEY CAN
SPEND ON A ROT OR ROD SO THERE
ARE FINE MOTOR PROBLEMS BUT
THERE'S NOTHING THAT YOU WOULD
LOOK AT AND SAY TH IS USE FOR
ANOTHER ANIMAL MADEL.
THERE'S NO OVER MUSCLE STIFFNESS
AND IT'S BECAUSE AT POST NATAL
DAY 7 WHEN THE BRAIN IS MOST
DEVELOPMENTALLY SIMILAR TO A
HUMAN BRAIN, PERINATALLY,
RODENTS ARE TODDLER STAGE.
ESSENTIALLY THEY'RE BEGINNING TO
WALK.
ADULT LIKE ROW COMEAU TIVE IS
POST NATAL DAY NINE BUT TWO DAYS
AFTER THIS THEY'RE BEGINNING
THAT THEY BEGINNING TO TRY TO
HAVE SUPPORT AT P2.
THIS IS NOT REALLY AN
APPROPRIATE MODEL.
WE NEED TO LOOK AT A MODEL WITH
A DEVELOPMENTAL TIMELINE THAT IS
MORE COMPARABLE TO HUMANS AND
THE RABBIT MODEL, I USE A RABID
PRENATAL MODEL IS A REALLY GO
AHEAD ONE BECAUSE RABBITS ARE
PERINATAL BRAIN DEVELOPERS LIKE
HUMANS AND YOU CAN EXERT THE
SYSTEM PRE-NATALLY SO I USE 70%
OR 80% GESTATION AND THEN YOU
CAN LOOK AT THE POST NATAL
DEVELOPMENT OF LOCOMOTION WHICH
IS ANOTHER PARALLEL IN THE
TIMELINE TO HUMAN
DEVELOPINGMENT.
THE INJURY OCCURS DURING THE
DEVELOPMENT OF THE CORTICAL
SPINAL PROJECTIONS SO IN TA
TARGET AREA I WAS MENTIONING IN
THE TIMELINE OF THE GENERAL
MOVEMENTS AND IT'S SIMILAR TO
HUMANS AND THIS IS AFTER THE
ESTABLISHMENT OF PROJECTIONS TO
THE SPINAL CORD LIKE IN HUMANS.
AS YOU CAN SEE FROM THIS PHOTO,
THIS IS A NEONATAL DAY ONE
RABBIT KIT AND IT'S DISPLAYING
STIFF MUSCLES IN ITS FORELIMB.
YOU CAN SEE THE STIFFNESS IS
CHANGING THE POSTURE OF THAT
FORELIMB AND WE SEE A VARIABLE
NUMBER OF LIMBS EFFECTED IN KITS
AFTER HI HYPOXIA HE IS KEEPIA SO
IT'S UNEFFECTED IF THEY DON'T
HAVE STIFFNESS IN THE LIMBS.
OVER ALL WE SEE THAT THE WHITE
MATTER AND THE OUTCOMES ARE ALSO
VERY SIMILAR.
RABBITS IN THE LAST PICTURE HAVE
STIFF MUSCLES AND THEY HAVE
HYPER REFLEXIA AND THERE'S A
REDUCTION IN THE RATE DEPENDENT
DEPRESSION OF REFLEX IN HUMANS.
THIS WAS FOUND TO BE THE MOST
ACCURATE PREDICTER OF SASS
ADVERTISE TEE AND THERE'S ALSO A
MAINTENANCE OF REFLEXER
RADIATION.
OVER ALL THE RABBIT IS AN IDEAL
MODEL TO DO THIS PRE CLINICAL
DEVELOPMENT OF TREATMENTS.
SO LET'S TAKE A LOOK.
WHAT ARE SOME OF THE PROMISING
PHARMACEUTICAL.
I WANT TO EMPHASIS I'M A SPINAL
CORD PHYSICALLOLOGIST, I THINK
THE SPINAL CORD HAS BEEN
OVERLOOKED IN RESEARCH.
CERTAINLY THE BRAIN INJURY
POSITIVE OF CEREBRAL PALSY BUT
DEVELOP YOU ARE NEURONS IN THE
BRAIN ARE NOT THE ONLY ONES THAT
ARE SENSITIVE TO A GLOBAL INSULT
LIKE NEURO INFLAMMATION AND THEY
CAN BE EQUALLY AS VULNERABLE TO
DEATH SO AFTER HIGH POX'
ISCHEMIA IN THE RABBIT AND IN
FACT IT'S BEEN DETECTED IN
POSTMORTEM SAMPLES IN THE SPINAL
CORD OF HUMANS AND WHO HAVE DIED
FROM HYPOXIA, AT BIRTH, THAT
THERE'S IT'S
IN THE SPINAL GRAY MATTER AS I
MENTIONED IN THE LAST SLIDE
THERE'S A REDUCED NUMBER OF
SPINAL MOTOR NEURONS.
ANOTHER THING WE FOUND IS A
LITTLE BIT OF A SURPRISE IS
THERE WAS AN EXPANSION IN THE
AFFERENTS.
SO THERE'S A SIGNIFICANT
EXPANSION IN INVASION INTO THE
IT COULD BE RELATED TO PRUNING
OF THE AFFERENTS AT FIRST.
THIS IS AN AREA THAT I'M VERY
INTERESTED IN PURSUING.
IT ALSO CAN BE RELATED TO THE
HIGH DEGREE OF CO-MORBIDITY WE
SEE IN CEREBRAL PALSY PATIENTS
WITH PAIN, CHRONIC PAIN IS A
FREQUENT OCCURRENCE.
THE PHO FOCUS TODAY IS SEROTONI.
IT INDICATED HERE BY THIS BLACK
SPROUT OF THE FIBERS AND THIS IS
ACCOMPANIED BY AN INCREASE IN
THE SEROTONIN CONCENTRATION IN
THE SPINAL CORD SO BOTH CERVICAL
AND LUMBAR A CORDS SHOW HIGHER
LEVELS OF SEROTONIN AND THIS IS
SOMETHING THAT IS VOLUME
TRANSMISSIONS SO AN INCREASE IN
THE SEROTONIN IN THE SPINAL CORD
COULD BE A BIG DEAL IN HOW IT
EFFECTS DEVELOPING NEURONS.
SO, IS IT A BIG DEAL?
IN FACT, IT IS.
IT'S ABSOLUTELY RELATED INFORM
THE MUSCLE STIFFNESS DIRECTLY
AND YOU CAN BLOCK SEROTONIN
RECEPTORS IN THE SPINAL CORD
USING A 5HT2 AND 5HD1 RECEPTORS
BLOCKER AND IT REDUCES STIFFNESS
SO RABBITS THAT HAD STIFF
MUSCLES HAVE REDUCED STIFFNESS
AFTER TREATMENT WITH
METHISERGIDE AND THERE'S NO
CHANGE IN THE STIFFNESS USING OF
A MEASUREMENT OF JOINT TORQUE
AND SO WE SEE THAT HYPOXY
ISCHEMIA CAN INCREASE LEVELS OF
SEROTONIN BUT IS THAT AN
BLOCKING IT, IS EFFECTIVE AT
REDUCING STIFFNESS OF THE
MUSCLES?
COULD IT BE THAT SEROTONIN AND
NOT THE HYPOXY ISCHEMIA IS
DRIVING MUSCLE STIFFNESS?
EARLY RESULTS FROM MY LAB
INDICATES THAT IT COULD BE.
INSTEAD OF HYPOXY ISCHEMIA,
THERE ARE A FEW PREGNANT RABBIT
DAMNS RELEASING SEROTONIN AND SO
JUST BY BOOSTING THE LEVEL OF
SEROTONIN IN SOME OF THESE KITS,
THEY HAVE AN INCREASED LEVEL OF
GIANT TORQUE.
AND INDICATING THAT MUSCLE
STIFFNESS IS DRIVEN BY SEROTONIN
ALONE WITHOUT THE HIGH TOX' HYPY
ISCHEMIA SO IT'S SOMETHING I
FIND VERY FASCINATEING AND IF
WORE GOING TO LOOK AT
PHARMACEUTICAL TREATMENTS BASED
ON SARAH TON INWE NEED TO KNOW
WHAT RECEPTORS SUB TYPES ARE
THERE AND HOW THIS IS EKKAPOL
CHANEFFECTING CELLS INTHE SPINAE
THERE ARE NO UNEXPECTED
OCCURRENCES.
SO I RECORDED FROM MOTOR NEURONS
AND THIS IS A CONTROL RABBIT
MOTOR NEURON AND INJECT AND I
CAN TELL THE INPUT AND OUTPUT
RELATIONSHIP BECAUSE THE MOTOR
NEURON WILL START FIRING AT A
CERTAIN AMOUNT OF CURRENT.
INTERESTINGLY ENOUGH, WHEN I PUT
SESEROTONIN IN THE BAT, THE MOTR
NEURONS ARE UNEFFECTED.
THIS IS IN CONTRAST TO AN HI
AFFECTED MOTOR KNEW ON AND THERE
IS A BIG CHANGE IN THE AMOUNT OF
CURRENT NEEDED TO ILLICIT ACTION
POTENTIALS AND A BIG CHANGE IN
THE THRESHOLD TO OVER ALL IF WE
LOOK, WE CAN COMPARE A CONTROL
MOTOR NEURONS IN THE BLUE BEFORE
AND AFTER AND THERE'S NO
SIGNIFICANT CHANGE IN REAL BASED
OR THRESHOLD BUT IF YOU LOOK AT
THE PINK AND RED TRACES THEY ARE
UNEFFECTED WITH STIFF MUSCLES OR
EFFECTED AND IN BOTH CASES, THEY
ARE SUPER SENSITIVE SO HI HAS
SOME EFFECT ON THE MOTOR NEURONS
OF CREATING SUPER SENSITIVITY TO
SEROTONIN.
SO, I WILL TAKE IT TO THE NEXT
LEVEL, I WANT TO SEE WHAT
SEROTONIN RECEPTORS ARE THERE IN
MEDIATING THIS.
THE FIRST ONE TO LOOK AT IS 5HT
RECEPTOR.
THEY'RE DESCRIBED IN ADULT MOTOR
NEURONS AND ADULT HUMANS WE KNOW
THAT THEY INCREASE EXCITE
ABILITY OF MOTOR NEURONS SO IN
OUR FIRST PASS, THIS IS JUST
PRELIMINARY DATA LOOKING AT
NEURONS IN THE VENTRAL CORD AND
WHERE MOTOR NEURONS ARE KNOWN TO
RESIDE THERE'S MORE STANDING OF
NEURONS.
IN THE HI SPINAL CORDS.
THIS IS A LIGHT BLUE VERSUS DARK
BLUE SO THERE ARE MORE NEURONS
IN GENERAL AND MOTOR NEURONS AND
POSITIVE FOR 5H2A MANY OF THE
5H1A IS INHIBITORY AND MEDIATES
NEURAL FATIGUE SO IT SHUTS DOWN
ACTIVITY IN THE MOTOR NEURONS
AND AS YOU CAN SEE FROM THE
SHAM, THE SPINAL CORDS, WE'RE
LOOKING AT THE VENTERRAL LATERAL
WHERE THE MOTOR NEURONS ARE
LOCATED.
THEY'RE STAYING GREEN AND THE
RED RING AROUND THE MOTOR
NEURONS INDICATES AN EXPRESSION
OF 5H21A RECEPTORS ON THE
MEMBRANE OF THE SHAM CONTROL
MOTOR NEURONS.
THAT RING OF RED STAINING IS
REALLY ABSENT WHEN WE LOOK IN
THE H1 MOTOR NEURONS.
INDICATING THAT THERE'S A LOSS
IN EXPRESSION OF THE 5H IT 1A
RECEPTORS.
SO, TO SUMMARIZE, IT SEEMS THAT
CONTROL MOTOR NEURONS IN THE
NEONATAL RABBIT HAVE AN OVER
ABUNDANCE OF 5HTA1 AND THEY
DOMINATE THE SEROTONIN BUT MUCH
OF THE RESPONSE IN NEONATES WILL
BE MIXED INHIBIT EXCITED AND NO
NET RESPONSE WHERE AN HI MOTOR
NEURON AND 2A RE SCEPTER MAY BE
THE DOMINANT RECEPTORS THAT
WE'RE HITTING WITH INCREASED
SEROTONIN.
AND 5H IT RE SCEPTER ACTIVATION
IN THESE MOTOR NEURONS WOULD
MEAN IT AMPLIFIES AND POST
POTENTIALS AND AMPLIFYING
INTRINSIC PERSIST APARTMENT AND
RECURRENCE THAT INCREASES EXCITE
ABILITY OF THE MOTOR NEURONS.
SO TO SUM SUMMARIZE, I THINK TE
BEEN OVERLOOKED FOR FAR TOO LONG
AND THEY'RE ALSO ENTERED IN
EFFECTIVE HYPOXY ISCHEMIA AND
OTHER GLOBAL INSULTS IT'S NOT
JUST THE BRAIN.
THE SPINAL SEROTONIN INCREASES
AFTER INJURY IN THE DEVELOPING
SPINAL CORD AND THIS COULD BE
VERY IMPORTANT BECAUSE BLOCKING
IT REDUCES HYPER TONIA AND
ACUTELY AND CHRONICALLY
INCREASING SEROTONIN USING SSRI
IS SUFFICIENT WITHOUT HYPOXIA TO
INDUCE HYPER TONIA AND THERE'S
5HD2 AND RECEPTORS AFTER HI
BASED ON OUR PRELIMINARY DATA SO
IN THE FUTURE I'M GOING TO LOOK
MORE CLOSELY AT WHETHER BLOCKING
I WANT TO THANK MY LAB FOR
HELPING WITH THIS WORK.
THIS IS A PICTURE OF MY LAB.
MY POSTDOC EMILY DID THE WORK.
AND MY OTHER TALENTED POSTDOC
AND CLASSIFYING SOME OF THE
RADIATION AND THINGS WE DIDN'T
HAVE TIME TO TALK ABOUT TODAY.
WE LOOK AT PEOPLE WITH CP AND
HELPS VERIFY WHAT WE'RE SEEING
IN THE ANIMALS IS SOMETHING THAT
IS RELIABLE IN PATIENT
POPULATIONS AND MY COLLABORATION
AND I'M CONVINCE TODAY HELP ME
IN THIS EVERY DOWN AND LOOKING
AT MOTOR UNIT DEVELOPMENT IN THE
SPINAL CORD OF THESE RABBITS.
THANK YOU.
>> GOOD MORNING, I'M Dr. GNAT
ALI MAITRE FROM EMILY AND
CHILDREN'S HEALTHCARE OF AT LAN
TA AND THE DIRECTOR OF EARLY
DEVELOPMENT AND CEREBRAL PALSY
RESEARCH.
I'M THRILLED TO BE HERE TO TALK
TO YOU TODAY ABOUT SOME OF OUR
RESEARCH AND THE PRIORITIES WE
SEE BEING IMPORTANT IN CEREBRAL
PALSY RESEARCH IN THE FUTURE.
THOSE KEY POINTS FOR CP RESEARCH
AT LEAST IN INFANCY, ARE TO
FOCUS ON SCIENTIFICALLY SOUND
RESEARCH SO MECHANISTICALLY
BASED, BOTH SAFE AND EFFECTIVE
RESEARCH IMPLEMENTABLE AND
IMPLEMENTED RESEARCH.
ILLINOILLINOIS STRAIGHT A STORYD
ICHD AND THIS IS CALLED APPLES,
A POSITIVE PARENT-FOCUSED
TRAINING FOR UPPER LIMB
EXPERIENCE WITH SENSORY MOTOR
FEEDBACK.
YOU WILL SEE THAT MY YOUNG
PATIENTS, MUCH LIKE THE APELS IS
IN THIS PICTURE ARE NUMEROUS AND
DIVERSE.
WHEN WE DESIGN INTERVENTIONS AND
WE TEST THEM, IN INFANTS WHO
HAVE CP VERY YOUNG, WE FACE
CERTAIN CHALLENGES THAT ARE
DIFFERENT THAN THOSE IN ADULT CP
RESEARCH.
WE'RE DEALING WITH RECENT
PERINATAL NURRAL INSULTS, MANY
OF THEM DUE TO PREMATURITY BUT
ALSO STROKE AND HIA.
THESE CAUSE A SYMMETRIC FORMS OF
CEREBRAL PALSY WHICH MEANS THIS
COULD BE OF A HEMOLPEGIA AND A
QUAD DRANK PLEDGE A, BOTH CAN
RESULT IN NON USE OF A MORE
EFFECTED HAND AND ARM.
THE LACK OF TYPICAL USE OF AN
ARM, AND THE LACK OF SENSORY
FEEDBACK TO THAT EXTREMITY
DURING A CRITICAL PERIOD,
ESPECIALLY VERY EARLY, CAN LEAD
TO A LOT TERRATIONS IN
DEVELOPMENT OF ASSOCIATED
FUNCTIONS BOTH MOTOR AND SENSORY
WELL INTO ADULTHOOD.
WE KNOW SOME OF THIS CAN HAPPEN
IN YOUNG INFANTS OR CHILDREN
WITH CEREBRAL PALSY.
THIS HAS BEEN SOME OF THE WORK
OF Dr. MATIRE SHOWING NEURAL
GENERATES IN THE BRAIN AND
STIMULI CAN BE ALTERED WHEN
CHILDREN ARE DEPRIVED OF SENSORY
FEEDBACK TO A LESS EFFECTED
EXTREMITY.
WE ALSO HAVE CHALLENGES IN
DESIGNING INTERVENTIONS AND THE
FACT THAT INFANT ENDURANCE AND
LEARNING CAPACITY ARE
NECESSARILY LIMITED BY
DEVELOPMENTAL PROCESSES.
WE ALSO FACE ANOTHER CHALLENGE.
WHICH IS THAT A YOUNG INFANT,
WITH CP, IS NOT JUST THE SINGLE
PATIENT THAT WE TREAT.
WE ARE ACTUALLY TREATING A
PARENT-CHILD DIALECT IN THE
SELF-CAPACITY IN THE LONG-TERM
OF THAT PARENT/CHILD DIE ADD
DEPENDS ON THAT STABLE AND
EMPOWERED RELATIONSHIP.
SO WITH ALL OF THESE CHALLENGES
IN MIND, HOW DID WE DESIGN AN
INTERVENTION AND TEST IT?
WE USED SCIENTIFIC SOUND BASIS
AND THIS IS FROM MY COLLEAGUES.
I WANT TO SHOWCASE THEIR WORK
AND HOW IT LED TO THE
DEVELOPMENT OF THIS
INTERVENTION.
WE USED A SOFT CONSTRAINTS AND
WE KNEW WE NEEDED A CERTAIN
DOSAGE OF IT, THANKS TO THE WORK
OF DOCTORS.
WE KN KNEW REACH TRAINING CAN
PROMOPROMOTES SUCCESS THROUGH SY
MITTENS.
SENSORY MOTOR TRAINING WAS
INSPIRED BY THE WORK OF Dr.
HEATH COCK AND FRIEL.
BIMANUAL PLAY BY THE WORK OF
Dr. GORDON AND NOT FOR
GETTING, THE ROLE OF PARENT
EDUCATION.
IN THE JUST-RIGHT CHALLENGE
SENSORY EXPOSURES, MIRRORED TO
PARALLEL SEQUENCES AND INFANT
LEARNING PRINCIPLES, ALL OF
THESE WERE BASED ON THE WORK OF
THE INCREDIBLE LATE Dr.
CASE-SMITH.
IN ADDITION, PARENT FEEDBACK
FROM EARLY PILOT STUDIES, PLAYED
A CRITICAL ROLE IN THE DESIGN OF
THE APPLE STUDY.
WHILE THIS WAS A RANDOMIZED
CONTROL TRIAL, WE ENDED UP
HAVING A WAIT LESS CONTROL
GROUP.
WHY?
BECAUSE PARENTS TOLD US THEY
WERE NOT WILLING TO PARTICIPATE
IN A STUDY WITH THEIR BABY WHO
HAD CEREBRAL PALSY UNLESS THEIR
CHILD HAD AN INTERVENTION.
WE HAD A FOUR-WEEK LONG
INTERVENTION THAT WAS ONLY AN
HOUR A DAY COMBINED OF ALL PLAY
ACTIVITIES.
AND THAT IS BECAUSE PARENTS TOLD
US THEY DIDN'T WANT TO SPEND
MORE THAN AN HOUR A DAY.
THIS HAD TO FIT IN THEIR NORMAL
ROUTINE AND NOT BE DISRUPTIVE TO
THEIR WORK-LIFE BALANCE AND IT
JUST COULDN'T FEEL LIKE TOO MUCH
EXTRA WORK.
IN ADDITION, TO INCLUDING BABIES
SIX TO 24 MONTHS OF AGE, WE THEN
FOCUSED ON PRIMARY OUTCOMES.
WHICH WANTED MECHANISTICALLY
BASED OUTCOMES.
THOSE THAT WE CAN GET FROM EEG
SUCH AS CORTICAL SEW MAT OWE
SENSORY FUNCTION AND SMOOTHNESS
OF REACH, BUT WE ALSO NEEDED TO
LOOK AT OUTCOMES THAT MATTERED
TO PARENTS AND THOSE ARE
PERFORMANCE OUT BECAUSE THEY TOS
WE KNOW BETTER WHAT THEY'RE
DOING A LOT A HOME THAN YOU CAN
AT A SINGLE TEST VISIT.
SO WE INCLUDED THE MOTOR LOCK
AND IN ADDITION TO ALL THESE
MEASURES OF CAPACITY AND
PERFORMANCE, AND
MECHANISTICALLY -BASED MEASURES,
WE NEEDED TO LOOK AT SAFETY
MEASURES.
FOR THE LESS EFFECTED EXTREMELY
THAT WAS GOING TO BE TESTED,
THAT WAS GOING TO BE RETRAINED
WE KNEW WE NEEDED TO BE CAREFUL
BASED ON PRIOR RESEARCH.
SO IN ADDITION TO SAFETY, WE
THEN HAD TO LOOK AT OUR
INTERVENTIONS AND WE WANTED TO
MAKE SURE THAT WE WERE
DELIVERING IT WITH RIGGER AND
FIDELITY WHICH REQUIRES THE
PARENT TO WRITE DOWN OR THROUGH
AN APP, TO TELL US HOW OFTEN AND
HOW WELL THEY'RE DOING THIS.
WELL, OUR PARENTS TOLD US WE
JUST CAN'T TAKE THE EXTRA TIME
EVERY SINGLE DAY TO LOG DAILY
USE, EVEN IN AN HOUR.
IT'S JUST TOO MUCH.
WE'RE GOING TO FORGET.
SO WE USED FIT BITS, WHICH IN
ADDITION TO LETTING US KNOW WHEN
THE MITTS WERE USED, WERE ABLE
TO QUANTIFY IT AND WE ALSO AT
EACH VISIT, VIDEOTAPED AND
MONITORED THE PARENTS ON
FIDELITY SHEETS TO MAKE SURE
THAT THEY WERE DOING THE
INTERCEPTINTERVENTION CORRECTLY.
WHAT HAPPENED IN APPLES?
IT'S FINISHED RIGHT?
THAT WAS THE FIRST FIVE YEARS OF
APPLES.
WE WERE ABLE TO ACHIEVE MORE
THAN WE THOUGHT.
FIRST, WE HAD INCREDIBLE
DIVERSITY AND CAPACITY IN OUR
FAMILIES THAT WERE ENROLLED.
WHILE OHIO, ESPECIALLY ALCOHOL ,
MAY NO NOT SEEM LIKE THE MOST
DIVERSE PLACE, WE WERE ABLE TO
ENHANCE DIVERSITY OF RECRUITMENT
IN OUR POPULATION AND YOU CAN
SEE THIS, WHILE OUR POPULATION
WAS 26% BLACK AND AFRICAN
AMERICAN, THE LOCAL POPULATION
WAS ACTUALLY LESS THAN 16%.
WE ALSO MADE SURE THAT OUR
FAMILIES HAD AN EDUCATIONAL
LEVEL THAT WAS REPRESENTATIVE OF
MANY DIFFERENT PEOPLE AND YOU
CAN SEE 50% OF THE POPULATION
HAD A HIGH SCHOOL DIPLOMA OR
LESS AND YET, WITH ALL OF THESE
THINGS, INCLUDING A MEDIAN BMSS
THAT IS SOCIALLY ECONOMIC LEVEL
THAT WAS IN THE LOW MIDDLE TO
POVERTY LEVEL, DESPITE ALL OF
THESE THINGS, THESE AMAZING
PARENTS WERE ABLE TO CARRY OUT
THE INTRA SELECTION WITH UTTER
COMPLIANCE AND YOU CAN SEE THAT
THE SCENE WHERE IT WAS 48 HOURS
A WEEK, WHEN WE ONLY REQUESTED A
MINIMUM OF 30 AND THEIR FIDEL
TEE TO THE INTERVENTION THAT WE
MEASURED EXCEEDED 95%
CORRECTNESS.
SO, WE KNEW WE COULD DO THIS
WITH A DIVERSE POPULATION AND
THEY WERE FULLY CAPABLE AND
WONDERFUL ABOUT IT.
SO, WHAT WERE THE OTHER
OUTCOMES?
WELL, GREAT.
ON EEG WE KNEW THAT THERE WAS A
GRAY AMP ATTI AMPLITUDE TO TOUCE
KNEW IT INCREASED COMPARED TO
OUR CONTROLS.
SAME THING WITH KINEMATICS AND
SAME THING WITH THE BAILEY UNI
MANUAL ITEMS.
WE HAD OUR MECHANISTIC AND OUR
EFFICACY MEASURES BUT WE ALSO
SAW THIS TREMENDOUS INCREASE IN
THE INFANT MOTOR ACTIVITY LOG
WHICH IS THE PARENT PERFORMANCE
MEASURES.
AND FINALLY, WE SHOW THAT THIS
WAS A SAFE INTERVENTION AND WE
WERE NOT ADVERSELY EFFECTING THE
CONSTRAINED EXTREMITY AND THAT
WE WERE NOT HINDERING GROSS
MOTOR DEVELOPMENT OR BUY MANUAL
DEVELOPMENT THROUGH OUR
INTERVENTION.
NOW SOME OF THE NEW AND MORE
EXCITING RESULTS.
WE ACTUALLY SHOWED THAT WE WERE
ABLE TO CHANGE THE NEURAL
PATTERN GENERATORS THE BRAIN IN
RESPONSE TO TOUCH AND MEANING
THESE BABIES ACTUALLY WERE ABLE
TO REWIRE THEIR SENSE OF TOUCH
IN THEIR MORE EFFECTED
EXTREMITY.
THE WAY WE DID THIS IS THROUGH
EEG.
WE DEVELOPED MAPS IN OVER 150
TERM, 150 TIP BEINGLY DEVELOPING
INFANTS WHO WERE MATCHED THROUGH
CORRECTED AGE AT TESTING AND
GESTATIONAL AGE AT BIRTH TO OUR
CP CHILDREN.
WHAT WE DID, WE CREATED TYPICAL
MAPS OF NEURO PATTERN GENERATORS
AND RESPONSE TO TOUCH.
WE THEN LOOKED AT OUR BABIES
WITH CP IN OUR INTERVENTION
GROUP AND OUR WAIT LIST
CONTROLLED GROUP.
WHAT WE WERE ABLE TO SHOW IS
THAT THESE MAPS WERE ACTUALLY
FITTING MORE, THESE BABIES WERE
SPENDING MORE TIMES IN NEURAL
PATTERN GENERATORS MAPS THAT
CORRESPONDED MORE TO THE
TYPICALLY DEVELOPING CHILDREN.
THE WAY THIS IS SHOWN HERE IS ON
THE LOWER PANEL.
IN THE INTERVENTION GROUP, THE
TOP LINE REPRESENTS BEFORE THE
INTERVENTION AND THE BOTTOM
AFTER.
THE FURTHER AWAY WE ARE FROM THE
BOTTOM OF THE FURTHER AWAY WE
ARE FROM A TYPICAL RESPONSE
THESE MAPS WERE SPENDING LESS
TIME AND WE DON'T FIT AS WELL
WITH THAT MAP OF NEURO PATTERN
GENERATORS TO TOUCH AND THERE'S
A BIG CHANGE.
IT CAN BE QUANTIFIED THROUGH
STATISTICS AND IT'S SIGNIFICANT.
THE WIT LESS CONTROL GROUP DID
NOT HAVE IT HAPPEN.
IT WAS WORSENING IN THE MONTH
DIFFERENCE BETWEEN THE TWO.
SO, IT WAS REALLY COOL.
SO WHAT WAS THE AFFECT OF
CHANGING THAT IMMEDIATELY AFTER
THE INTERVENTION?
FOR THE FIRST TIME, WE'VE BEEN
ABLE TO SHOW, TO FOLLOW THREE
YEARS OF UP TO THREE YEARS OF
AGE THESE BABIES AND R. S REMEME
STARTED AT SIX MONTHS AND SOME
STARTED AT 24 MONTHS BUT WE
FOLLOWED ALL OF THEM TO THREE.
I'M SO EXCITED BECAUSE FOR THE
FIRST TIME WE WERE ABLE TO LOOK
AT TRAJECTORIES OF DEVELOPMENTS.
THANK YOU CAN SEE IN YELLOW,
THIS COHORT OF TYPICALLY
DEVELOPING MATCHED CHILDREN FOR
GESTATIONAL AGE AND CORRECTED
AGE AT TESTING TIME.
NO SURPRISE, THIS IS THE
TRAJECTORY OF THIS MILESTONE
ACQUISITION IN ONE EXTREMITY
WHICH WAS THEIR DOMINANT ONE, IT
WAS RANDOMLY A SIGNED.
NO SURPRISE, IT'S LINEAR ACROSS
TIME.
WE HAVE THE NUMBER OF MONTHS
CORRECTED AGE AND HERE WE HAVE
THE NUMBER OF DEVELOPMENTAL
SKILLS.
WHEN WE LOOK A LOT PATIENTS WHO
HAVE CEREBRAL PALSY AND WHO DID
NOT RECEIVE APPLES, SO THIS WAS
OFTEN THE FIRST POINT OF
TESTING, OR SOME OF THE POINTS
IN THE WAIT LIST GROUP.
THIS IS ALSO NO SURPRISE.
THERE'S A TRAJECTORY THAT GOES
FURTHER AND FURTHER AWAY FROM
THE TYPICALLY DEVELOPING
CHILDREN.
MANY INCREDIBLE RESEARCHERS SOME
OF THEM AT THIS WORKSHOP HAVE
ALREADY SHOWN THAT THE
TRAJECTORY OF UNI MANUAL SKILLS
IN A MORE EFFECTED EXTREMITY
WILL DIVERGE OVER TIME AND THEN
WE HAVE THE BABIES WITH APPLES.
AND OVER TIME THAT REWIRING OF
THE BRAIN AND THE SKILLS THAT
THEY ACQUIRED EARLIER, ACTUALLY
STARTED TO GET THEIR TRAJECTORY
CLOSER TO THAT OF TYPICALLY
VEMMING CHILDREN.
SO IT'S NOT PERFECT, I KNOW.
THIS CAN BE QUANTIFIED IN
ANOTHER WAY.
IF WE LOCK AT THE NEW MILESTONES
ACQUIRED PER MONTH, TYPICALLY
DEVELOPING CHILDREN ACQUIRE
BETWEEN .5 AND 1.
WHEREAS, OVER THE COURSE OF
THREE YEARS, WHEREAS OUR BABIES
WITH CP AND APPLES, THIS IS
CLASSIFIED ACCORDING TO TMSCS
AND SOME OF THEM MORE.
YOU THINK BUT THEIR SCORES WON'T
HIGHER AND THEY STARTED OFF
LOWER.
WE KNOW OUR INTERVENTION IS
WORKING AND IT'S WORKING IN THE
LONG-TERM AND IT PROBABLY JUST
KEEPS IN SUMMARY IT'S POSSIBLE
TO DESIGN AN INTERCEPTIONS THAT
IS SCIENTIFICALLY SOUND,
MECHANISTICALLY BASED THAT IS
SAFE, EFFECTIVE, GENERALIZABLE
THAT HAS PARENT EMPOWERMENT AT
ITS CORE AND, HOWEVER, WITH ALL
OF THIS, WE ALSO SAW THAT THERE
WERE SO MANY MORE OPPORTUNITIES
FOR IMPROVEMENT.
WE NEEDED TO MAKE THIS BETTER.
TO GET THOSE TRAJECTORIES TO
FULLY CLOSE.
BUT THE FIRST THING IS, WE CAN'T
WAIT.
WE HAVE TO DELIVER SOMETHING
THAT WORKS.
THE FIRST THING WAS DISSEMINATE
AND THE WAY WE DO IS IS BY
LEVERAGING STAKEHOLDER FEEDBACK.
FROM LARGE SYSTEMATIC REVIEWS OF
INTERVENTIONS THAT WE CAN
CONDUCTED, THANKS TO THE
CEREBRAL PALSY FOUNDATION.
WE SAW ACROSS MANY DOMAINS THAT
INTERVENTIONS THAT OUR PARENT
DELIVERED ARE THOSE THAT ARE
STAKEHOLDERS WANTED.
ABOVE THOSE BY THERAPISTS AND
CERTAINLY MORE THAN THOSE THAT
ARE SURGICAL OR MEDICAL.
WE ALSO DID A NATIONAL SURVEY OF
PARENTS AND INDIVIDUALS WITH
DISABILITIES.
AND THEY SAID AFTER EVEN MILD
PERINATAL INSULTS, THEY VALUE
DYADIC FAMILY INTERACTIONS HAS A
TOP PRIORITY IN OUTCOMES AND IN
DESIGN.
AND THEN WHEN WE DID STUDY
PARTICIPANT FEEDBACK, WE SAW,
AGAIN, THAT PARENTS WANTED
OUTCOMES THAT MATTERED IN THEIR
DAILY LIVES.
AND PROVIDERS WHO VALUE THEM AS
TEAM MEMBERS.
SO BEFORE IMPROVING APPLES, WITH
ALL OF THIS, WE KNEW THAT FIRST,
WE NEEDED TO BUILD CAPACITY TO
GO YOUNGER AND GET MORE FEEDBACK
AND FOR THAT WE NEEDED TO BUILD
EARLY DETECTION CAPACITY IN
HIGH-RISK INFANT FOLLOW-UP
SETTINGS AND IN THE COMMUNITY.
SO THESE INTERVENTIONS COULD
START EARLIER AND IN AN INFANT'S
LIFE.
WE NEEDED TO CREATE A PIPELINE
FOR RAPID KNOWLEDGE TRANSLATION
AND DISSEMINATION TO PARENTS AND
PROVIDERS SO IF AN INTERVENTION
IS SAFE AND EFFECTIVE, WE CAN
THEN START EARLIER AND THEN
START WORKING ON IMPROVEMENTS AT
THE SAME TIME AS WE'RE
DISSEMINATING THE EARLIER
VERSION OF IT.
SO HOW DID WE DO THIS?
HOW DID WE MEET THESE NEEDS?
WE PARTNERED WITH THE CEREBRAL
PALSY FOUNDATION AND THEY'VE
BEEN INCREDIBLE BECAUSE WE'VE
BEEN ABLE TO, ACROSS A LARGE
NETWORK OF HIGH-RISK INFANT
FOLLOW-UP PROGRAMS IN THE UNITED
STATES, DECREASE THE AGE AT
EARLY DETECTION, BELOW THE AGE,
BELOW 12 MONTHS CORRECT TO DATE.
THIS, DESPITE THE IMPACT OF
COVID, IT STABILIZED AND I CAN
TELL YOU 2022 NUMBERS ARE RIGHT
AROUND NOW THAT 11-MONTH MARK.
AND THEY ALSO HELPED US CORRECT
A CONFERENCE AND SUMMIT THAT
FOCUSES ON JUST ON DETECTION
ANDER SEDEANDINTERVENTION BUT I.
THESE ARE SOME THE TOOLS WE USE,
IMPLEMENTATION SCIENCE, NETWORKS
EDUCATIONAL TOOLS AND
IMPLEMENTATION TOOLS THAT ARE
BEING DISSEMINATED FOR SEVERAL
RESULTS, FIRST, IN ADDITION TO
DECREASING THE AGE AS CP
DIAGNOSIS TO LESS THAN 12
MONTHS, WE ALSO MADE SURE THAT
OVER 4,000 PROVIDERS WERE
TRAINED IN EARLY DETECTION
INTERVENTION.
MORE THAN TWO DOES TRAINERS NOW
ARE CONTINUOUSLY INCREASING THE
CAPACITY AND THE SYSTEM.
WE'RE ALSO THROUGH THE CPF,
THEY'RE PARTNERING WITH OTHER
FOUNDATIONS IN THEIR EFFORTS AND
THEY'RE HELPING THE UCP OR THE
CPA, ACHIEVE THEIR OWN GOALS.
AND THEN WE HAVE A CONSENSUS
STATEMENT THAT WE PUBLISHED.
IF WORE GOING TO DESIGN EARLIER
INTERVENTIONS WE NEED TO START
WITH A DESIGNATION THAT EVERYONE
CAN AGREE ON FOR HIGH-RISK OF
CEREBRAL PALSY.
SO WE ENGAGE LEADERS ACROSS ALL
OF NORTH AMERICA AND WE HAVE
THIS ENORMOUS CONSENSUS
STATEMENT THAT WE PUBLISHED ON
WHAT THAT CONSTITUTES.
SO WE CAN START INTERVENTIONS
EARLIER.
AND SOME OF THESE PEOPLE ARE
ACTUALLY AT THIS WORKSHOP.
HEY, STACEY.
THE FOURTH RESULT IS THAT WE
WERE ABLE TO TRAIN WITHIN ONE
YEAR OVER 100 COMMUNITY
PROVIDERS IN APPLES
ADMINISTRATION AND TOOLS.
WITHIN ONE YEAR OF PUBLICATION.
AND SO, WHILE IT'S NOT PERFECT,
APPLES, AT LEAST IT'S GETTING
OUT THERE AND PEOPLE ARE GETTING
TRAINED IN IT.
AND THIS ALLOWS US TO NOW MOVE
TO THE COMPETING RENEWAL WHICH
YEAH, THANK YOU NIH GOT FUNDED
AND IT'S IMPROVING ON APPLE'S
TELLING AND WE KNOW THAT 15
MONTHS SEEMS TO BE THAT THE
TIPPING POINT IN WHEN THE
INTERVENTION WORKS BEST, WE CAN
START BELOW THAT AND TELEHEALTH
WHICH HAS SHOWN TO BE FEASIBLE
AND EFFECTIVE AS A DELIVERY TOOL
HAS SOME STANDARDIZATION ISSUES
AND HAS SOME OTHER ISSUES THAT
WE CAN ADDRESS BUT WE STUDIED
THAT AND IT COULD PROVIDE A
VIABLE ALTERNATIVE IN TREATING
AN INFANT WITH CP.
AND WE ALSO KNOW THAT PARENT
INTERVENTIONS COULD INCREASE THE
EFFECT OF INFANT INTERVENTIONS
SO THIS TIME THE GOAL OF APPLES
TELE IS NOT JUST TO IMPROVE HAND
AND ARM USE IN BABIES, 12 MONTHS
AND UNDER, WITH CP OR HIGH-RISK
FOR CP, VIA TELEHEALTH OR
IN-PERSON.
IT'S ALSO TO EMPOWER PARENTS
THROUGH KNOWLEDGE, PARENTING
SKILLS AND PRACTICE.
AND TO TARGET OUR INTERVENTIONS
TO DETERMINE WHICH DYADS MIGHT
BENEFIT FROM PARTICIPATING
INTERVENTIONS BEFORE THEY HAVE
INTERVENTIONS, MOTOR
INTERVENTIONS AND SO IN CLOSING,
WE HAVE APPLES TELE WHICH IS A
DESIGN NOW THAT INCORPORATES
EVERYTHING I'VE TOLD YOU ABOUT.
267 PARTICIPANTS ACROSS FOUR OF
THE NETWORK SITES OF EARLY
DETECTION.
OUR OUTCOMES INCLUDE MANY
PARENTING OUTCOMES, THE ONES
THAT THEY WANTED ABOUT DYADS AND
PARENTS AND ALSO PERFORMANCE IN
THE HOME AND SOME STANDARD ONES.
THERE'S THREE GROUPS.
ONE GETS BUSINESS AS USUAL BUT
REMEMBER, THEY WANT THAT
INTERVENTION EITHER.
SO THEY GET TO CHOSE AFTER THAT
WHATEVER INTERVENTION THAT THEY
WANT.
PARENTING OR MOTOR.
AND THERE'S ONE THAT GETS THE
APPLE TELE INTERVENTION FIRST
AND THE LAST THAT GETS THE
PARENTING INTERVENTION FIRST.
THERE'S ALSO COST EFFECTIVENESS
AND AN SIL AR STUDY AND THE
REPOSITIVITY FOR ALL AI ANALYSIS
AND WORE DOING WELL.
12 PARTICIPANTS WERE RECRUITED
IN THE LAST TWO MONTHS AND NOW
THAT WE'VE HAD THIS OUTPOURING
FROM A COUNTRY WIDE FEEDBACK
FROM PARENTS, WE ARE ACTUALLY
HAVE 10 THIS COMING MONTH.
SO WHAT IS NEXT TO DEVELOP
APPLES NEXT-GEN THANKS TO WORK
ABOUT NIH FROM NIH FUNDED
RESEARCHERS AT THIS WORK SOLVE
AND WE ALSO NEED TO EXPAND
KNOWLEDGE TRANSLATION AND
DISSEMINATION AS WE GO WITH OUR
FOUNDATION PARTNERS.
WE HAVE LEVERAGED ALL OF THIS TO
BECOME THE NEURO DEVELOPMENTAL
CORE FOR THREE LARGE MULTI
CENTERED TRIALS, ALLOWING
EXPANSION OF CP RESEARCH THROUGH
OTHER TYPES OF TRIALS AND WE ARE
USING SOCIAL MEDIA TO DELIVER A
MOTOR INTERVENTION WITH THE CPF
AND UNICEF.
SO MY KEY POINT, IN ADDITION, TO
THANKING SO MANY PEOPLE THAT ARE
RIGHT THERE, IS THAT IF WE'RE
GOING TO FOCUS ON CP RESEARCH
AND INFANCY, WE CAN FOCUS
ESPECIALLY ON SCIENTIFICALLY
SOUND RESEARCH AND THAT BOTHERS
TO BE SAFE CONNECT TIVE
IMPLEMENTABLE AND IMPLEMENTED.
I HOPE YOU WILL SEE THE VALUE OF
THIS AND THANK YOU SO MUCH FOR
YOUR TIME AND ATTENTION.
>> HELLO MY NAME IS BERNADETTE
GILLICK.
I'M FROM THE UNIVERSITY OF
WISCONSIN MADISON.
AND I'M LOOKING FORWARD TO
SPEAKING TO YOU TODAY ON THIS
STRATEGIC PLAN PRIORITY AREA ONE
BASIC AND TRANSLATIONAL RESEARCH
ABOUT CORTICAL PLASTICITY AND
HOW THAT RELATES TO RECOVERY
FROM NEWER LOGIC INSULT IN
ADULTS AND PEDIATRIC
POPULATIONS.
THANK YOU VERY MUCH FOR THE
INVITATION TO PRESENT.
THANK YOU TO ALL WHO ARE
ORGANIZING THIS EVENT AND I LOOK
FORWARD TO THE OTHER TALKS AS
WELL.
SO, RELATE TO GO THE PRIORITY
AREAS AND RECOMMENDATIONS OF THE
2017 STRATEGIC PLAN, THERE'S A
LOT OF OVERLAP WITH CORTICAL
PLASTICITY AND I CHOSE TO
HIGHLIGHT HERE A FEW OF THE
DIFFERENT AREAS THAT THIS TALK
WILL ENCOMPASS AND HAVE BASIC
THREADS THROUGH INCLUDING
TRANSLATIONAL RESEARCH, BASIC
RESEARCH AND CLINICAL RESEARCH
AND IN UNDERSTANDING AND
UTILIZING NEURO PLASTICITY AND
ALSO CONSIDERING THE LIFESPAN
AND ENHANCING TREATMENT OPTIONS.
THE ADAPTIVE CAPACITY OF THE
CENTRAL NERVOUS SYSTEM AND THAT
NEURONS CAN ALTER THEIR
STRUCTURE AND THEIR FUNCTION SO
THROUGH INTERNAL SIGNALS AND
EXTERNAL SIGNALS, THAT STRUCTURE
AND FUNCTION CAN BE CHANGED.
AND NEURO PLASTICITY IS THE
MECHANISM IN THE BRAIN IN CODES
EXPERIENCES AND LEAPS NEW
BEHAVILEARNS NEW BEHAVIORAND DAT
BEHAVIOR OR DEVELOP AND CONTINUE
TO DEVELOP IN THE FACE OF THIS
DAMAGE.
SO, WHAT HAPPENS OVER THE
LIFETIME AND THE LIFESPAN OF AN
INDIVIDUAL IN TERMS OF PLASTIC
CAPACITY WITHIN THE CORTEX AND
HOW THEY MAY ACTUALLY RECOVER
FROM A NEWER LOGIC INSULT.
SO THERE'S A COUPLE WAYS TO
DEFINE THE POTENTIAL OF NEURO
PLASTICITY TO BE ADAPTIVE IN
THAT WE CAN LEARN NEW SKILLS OR
RESTORE LOST FUNCTION AND ALSO
MALL ADAPTIVE IN TERMS OF THE
PLASTICITY OF THE NERVOUS SYSTEM
LEADING TO A DISRUPTION IN
FUNCTION.
SO AS I SAID, NOT ALL PLASTICITY
IS GOOD.
SO FOCAL DYSTONIA, LIMB PAIN,
SEIZURES, THESE ARE ALL
POTENTIALLY MALL ADAPTIVE
COMPONENTS OF PLASTICITY THAT
CAN OCCUR.
SO WE ALSO WANT TO LOOK AT HOW
WE MEASURE NEURO PLASTICITY AND
THE TIME SCALES.
HOW EASY IS IT TO DO?
SO ON SHORT TERM SCALE IN MILLI
SECONDS OR SECONDS, YOU ARE
PROBABLY VES CAL OR NEURO
TRANSMITTER RELEASE CAN BE
MEASURED AND ON THE SHORT TIME
SPAIN IT'S A CHALLENGING THING
TO DO ESPECIALLY IN HUMANS AND
THE LONGER TERM IN TERMS OF
MINUTES OR HOURS, YOU CAN
MEASURE THE INCREASE DENSITY OF
RECEPTORS AND THE POST SYNAPTIC
MEMBRANE CHARGING IN HUMANS TO
DO OR BEHAVIORAL PLASTICITY.
IN TERMS OF WHAT WE SEE IN WEEKS
AND MONTHS AND YEARS AND
REHABILITATIONS AND THAT'S MORE
FEASIBLE AND MAY BE AN INDICATOR
OF THE PROCESSES THAT WE TALKED
ABOUT THAT ARE MORE CHALLENGES
AGAIN IN MEASURING IN HUMANS.
PEOPLE OFTEN DISCUSS AND I OFTEN
TALK ABOUT IS A PEDIATRIC BRAIN
MORE PLASTIC THAN AN ADULT
BRAIN?
AND I TYPICALLY GO BACK TO THE
CONNARD PRINCIPLE OF A
NEUROLOGIST WHOSE STATEMENT IN
GOOD RESEARCH IN THE 1930s AND
40s IN INFANT MONKEYS SHOWED
THERE'S A NEGATIVE LINEAR
RELATIONSHIP BETWEEN THE AGE AND
FUNCTIONAL OUTCOME.
THIS QUOTE IS SHARED AND THE
YOUNGER THE LEASH AN ORGANISM
THE BETTER THE OUTCOME.
HOWEVER, SHE ALSO SHOWED THAT
ADULT PRIMATES WITH STROKE SORRY
BRAIN LESIONS CAN ALSO EXHIBIT
SIGNIFICANT SPARING AND RECOVERY
OF FUNCTION, ESPECIALLY IN THE
LESIONS ARE IN STAGES AND NOT
ALL AT ONCE.
THE JURY IS OUT IN TERMS OF
PEDIATRIC BRAIN MORE PLASTIC
THAN IN AN ADULT BRAIN, IT
DEPENDS ON THE INJURY AND WHEN
AND WHEN IT OCCURRED.
THIS IS AN ARTICLE ON SA
REMEMBER RAL PLASTICITY FOR THE
DEVELOPING BRAIN FROM ISMAIL AND
IT GIVES A REALLY INTERESTING
DEPICTION OF THE DIFFERENT
FACETS OR PATTERNS OF NEURO
PLASTICITY AND SO I MENTIONED
ADAPTIVE AND MALL ADAPTIVE BUT
IF YOU BREAK IT DOWN NO
DEVELOPMENTAL ADAPTIVE,
REACTIVE, EXCESSIVE
DESTABILIZEING AND THE
VULNERABILITY OF THE CENTRAL
NERVOUS SYSTEM YOU CAN SEE THE
DIFFERENT ASPECTS OF HOW NEURO
PLASTICITY CAN BE DEFINED.
HOW IS IT TYPICAL OR ATYPICAL AS
STATED HERE NORMAL OR IMPAIRED
AND HOW IS IT DEPENDING UPON THE
INJURY THAT MIGHT HAVE OCCURRED?
IN THIS ARTICLE, THEY GO ON TO
TALK ABOUT THE TARGETS THAT HAVE
BEEN SHOWN TO CONTRIBUTE MOTOR
SENSORY IMPAIR.
AND PATIENTS WITH CEREBRAL
PALSY.
AND SO WHEN WE LOOK AT ALL OF
THESE DIFFERENT TARGETS,
INCLUDING THE CORTICAL SPINAL
TRACT, AND OTHER TRACKS, IS IT
REALLY TIME TO ADOPT A MULTI
MODAL BEHAVIORAL PHARMACOLOGICAL
OR STIMULATION-BASED
MULTI-TARGETED NEURO MODULAR
APPROACH TO BEHAVIORAL OUTCOMES
AGAIN WITH THE CORTICAL
PLASTICITY.
I'LL TAKE A MODEL OF ADULT
STROKE WHERE WE HAVE ISCHEMIA
AND STROKE.
YOU CAN SEE HOW THERE ARE
VARIATIONS IN TERMS OF HOW THE
STROKE MIGHT HAVE IMPACTED
INDIVIDUALS WHO ARE CHILDREN OR
ADULTS.
IF WE TAKE THAT MODEL AND ADULTS
AND APPLY IT TO EARLY INJURY IN
STROKE AND CEREBRAL PALSY, WE'RE
WORKING WITH A MUCH DIFFERENT
TYPE OF ENVIRONMENT.
SO, EARLY INJURY TO THE BRAIN OR
STROKE IS A COMMON CAUSE OF
CEREBRAL PALSY.
AND CEREBRAL PALSY AS WE KNOW IS
THE MOST COMMON MOTOR DISABILITY
IN CHILDHOOD.
SO, THE TWO DIFFERENT MODELS,
ADULT STROKE AND PEDIATRIC
STROKE ARE THE STROKE PERINATAL
STROKE, HAVE DIFFERENT
APPROACHES IN TERMS OF HOW WE'RE
UNDERSTANDING CORTICAL
PLASTICITY.
AND WHEN WE LOOK AT THE
INCIDENTS OF STROKE IN ADULTS,
THE THOUSAND OUT OF 100,000 AND
THE CHANGE OVER THE LIFESPAN IF
YOU ACTUALLY DECREASE THE AGE,
FROM CHILDHOOD, ONE TO TWO IN
100,000, BUT ACTUALLY PERINATAL
STROKE 40 IN 100,000, YOU CAN
SEE THAT THE INCIDENTS ITSELF IS
INDICATIVE OF VARIATIONS IN
TERMS OF THE AGE OF THE
INDIVIDUALS AND ALSO WHERE THEY
ARE IN THEIR DEVELOPMENTAL
PHASES AS WELL.
HERE IS A PICTURE OF TWO
DIFFERENT MRIs, THE PERSON ON
THE LEFT IS A FEMALE,
35-YEAR-OLD FEMALE, DEVELOPING
AND THE PERSON ON THE RIGHT IS A
THREE--YEAR-OLD FEMALE
DEVELOPING.
YOU CAN SEE AS A NEURO SCIENTIST
OR RADIOLOGIST THAT THE
DIFFERENCE OF COURSE IN BRAIN
STRUCTURE AND AGE BUT YOU CAN
ALSO APPRECIATE THAT THESE TWO
DIFFERENT INDIVIDUALS ARE
DIFFERENT TIMEFRAMES IN THEIR
OWN DEVELOPMENT AND SO NOW HERE
IS TWO DIFFERENT MRI IMAGES.
ONE IS ADULT HAVING A STROKE ON
THE LEFT AND ANOTHER OF A CHILD
WITH A STROKE ON THE RIGHT AND
ALTHOUGH THEY'RE IN DIFFERENT
LOCATIONS AND DIFFERENT SIZES,
THE POINT BEING THAT THE STROKE
IS GOING TO INFLUENCE A BRAIN
THAT IS POTENTIALLY DEVELOPING
IN A MUCH DIFFERENT TIMEFRAME IN
THEIR LIFE.
AND I SHOWED THIS PICTURE
BEFORE.
THESE ARE 30 INDIVIDUALS WITH
WHOM WE WORKED IN OUR STUDIES
AND THIS IS FROM JESSICA CASSIDY
AND NER EARLY WORK WITH US.
IT SHOWS THE VARIATION IN
THOUSAND THAT STROKE CAN PRESENT
ITSELF TOO.
A VARIATION IN TERMS OF CORTICAL
PLASTICITY DEPENDING ON THE
LESION SIZE AND THE LESION
BURDEN OVER ALL.
THE POINT IS THAT IN ADULTS, WE
HAVE RECOVERY AND REORGANIZATION
AFTER EARLY STROKE.
AND AFTER STROKE AND THE ADULT
BRAIN.
BUT WHEN WE LOOK AT THE
PEDIATRIC BRAIN, WE HAVE
RECOVERY AND DEVELOPMENT SO IT
MAY NOT ACTUALLY SHALL
REORGANIZATIONS THAT WE'RE
TARGETING IT'S ACTUALLY
ORGANIZATION.
AND THE WAY THAT THE BRAIN IS
RECOVERING IS ACTUALLY
RECOVERING ALONG WITH
DEVELOPMENT AT THE SAME TIME.
MUCH DIFFERENT THAN A STROKE
IMPRESSED ON A MATURE, ADULT
NERVOUS SYSTEM.
THE INTERSECTION NOW OF NEURO
PLASTICITY IN NEURO MODULATION
ALLOWS US TO LEARN MORE.
THIS IS NEURO MODULATION IN
TERMS OF THE SPECTRUM OF THE
TECHNIQUES THAT WE HAVE OUT
THERE.
BEHAVIORAL NEURAL MODULATION AND
THE MOVEMENT THERAPY IS ONE OF
THOSE TYPES.
FARM CO LOGIC WITH THE CENTRAL
NERVOUS ACT MEDICATION THAT'S
INFLUENCE ESSENTIAL NERVOUS
SYSTEM AND ELECTRICAL NEURO
MODULATIONS SUCH AS TRANCE
CRANIAL DIRECTING CURRENT
STIMULATION OR SPINAL CORD
STIMULATION AND THE USE OF A
MAGNETIC FIELD LIKE REPETITIVE
TIM STIMULATION OR STEM CELL
TRANSPLANTS AND WHAT ARE THE
TYPES OF TECHNIQUES USED IN
ADULT AND PEDIATRICS THERE'S
THREE I WILL SHARE WITH YOU
TODAY.
ONE IS THE TRANCE CRANIAL DIRECT
CURRENT STIMULATION ON THE LEFT
AND THERE'S ANNAN OAT AND CATH
OAT AND WE'RE STIMULATING THE
BRAIN TO LONG-TERM INFLUENCE
FACILITATION INHIBITION.
TMS CAN DELIVER PULSES OF
ELECTRO MAGNETIC INDUCTION THAT
ACTUALLY ALLOW US TO UNDERSTAND
THE RESPONSE OF THE BRAIN TO
THOSE PULSES OR EVEN INFLUENCE
IT.
WE DO THOSE PULSES REPETITIVELY.
AND THEN THERE'S ALSO THE VIENNA
SYSTEM THAT I'LL TALK ABOUT IN
TERMS OF SPECIALIZING THE
ELECTRODES TO DELIVER ELECTRICAL
PULSES AND IT'S A BOTTOM-UP
APPROACH BECAUSE YOU STIMULATE
THE NERVE TO INFLUENCE THE
ACTIVITY OF THE CENTRAL NERVOUS
SYSTEM.
SO TRANCE CRANIAL MAGNETIC
STIMULATION THERE'S A STIMULATER
THAT I WILL IS ITS A RESPONSE
THAT THE RESPONSE I'M TALKING
ABOUT TODAY IS THE MOTOR EVOKED
RESPONSE AND WHEN WE LOOK AT
THIS THIS IS FROM A CHILD
WORKING WITH US IN OUR LAB.
WE CAN MEASURE THE AMPLITUDE AND
LOOK AT IT OVER TIME AND LOOK AT
IT BEFORE AND AFTER INTERVENTION
SO WE CAN REALLY ASSESS WHAT IS
HAPPENING WITH BRAIN PHYSIOLOGY.
AND BRINGING UP HERE SOME GREAT
WORK BY KATHY, AT THE UNIVERSITY
OF AUCKLAND IN TERMS OF USING
TMA IN ASSAULT STROKE.
IN TERMS OF AN ALGORITHM TO
PREDICT WHAT IS HAPPENING WITH
RECOVERY, YOU CAN SEE HERE
THERE'S MILD, MODERATE AND
SEVERE STROKE AND SHE USED TMS
TO UNDERSTAND HOW MUCH OR WHAT
IS THEIR PERCENTAGE OF MACHINE
MAXIMUM IMMEDIATED TO' LITT' ELT
AND IT GIVES YOU A WINDOW INTO
THE BRAIN TO THE EXCITE ABILITY
OF THE BRAIN AS IT RECOVERS
AFTER THE STROKE.
THAT ALGORITHM EXTENDS WHERE SHE
ACTUALLY INTEGRATES THAT MOTOR
VOLKSWAGEN POTENTIAL OUTCOME TO
UNDERSTAND WHAT THE POTENTIAL IS
FOR RECOVERY.
SO THEY'RE PREP 2 ALGORITHM
INCORPORATES THAT TMS IN MOTOR
EVOKED POTENTIAL.
THOSE PREDICTORS ALLOW A
DESCRIPTION OF THE OUTCOME.
SOMETHING DESCRIBE THEM TO USE
IN THE DISCUSSIONS WITH
PATIENTS.
AS WELL AS A FOCUS OF
REHABILITATION IN TERMS OF WHAT
SHOULD BE THE INTERVENTION AND
SHOULD THIS ACTUALLY BE GEARED
TOWARDS REHABILITATION
COMPENSATION AND OTHER
ACTIVITIES.
WE ALSO USE TMS WITH INFANTS AND
SOME OF THE WORK THAT I'M DOING
NOW TO MEASURE THE EXCITE
ABILITY AFTER EARLY BRAIN INJURY
SO WHETHER IT BE IN THE NICK YOU
ON THE LEFT OR THE LAB ON THE
RIGHT WE TRIED TO HAPPEN THE
BRAIN AS IT IS RECOVERING AFTER
EARLY PERINATAL INJURY.
THIS IS SOME OF THE WORK OF ALAN
SUITER A PPHD CANDIDATE LOOKING
AT SIMULATIONS OF THE ELECTRIC
FIELD INDUCES AND TRYING TO
UNDERSTAND WHAT WOULD OCCUR IF
WE STIMULATED AN INFANT BRAIN SO
ADULT BRAIN ON THE LEFT AND
FOUR-MONTH-OLD IN THE MIDDLE AND
24-MONTH-OLD SCAN OF AN INFANT
LOOKING AT WHAT WOULD BE THE
ELECTRIC CURRENT AND THE CURRENT
DENSITY.
WE CAN USE THIS TO ACTUALLY
UNDERSTAND HOW INFANT IS
DEVELOPING OVER TIME AND ON THE
LEFT IS THIS INFANT IS FOUR
MONTHS OLD CORRECTED AGE ON THE
RIGHT THEY'RE 14 MONTHS OLD.
AND WE CAN LOOK AT HOW THAT
MOTOR EVOKED POTENTIAL IS
CHANGING AND HOW THE SIGNAL IS
CHANGEING AND HOW THEY'RE
RESPONDING TO THE SIGNAL.
AS THEY DEVELOP AND HO AS WE
MEASURE BEHAVIORAL ASSESSMENTS
AS WELL.
SO WE HAVE A CURRENT STUDY
FUNDED BY A NIH RO1 BY THE NICHD
AND NINDS THAT LOOKS AT THE
RECOVERY OVER THE FIRST TWO
YEARS OF LIFE.
USING TMS AND MRI IN BEHAVIORAL
ASSESSMENTS WE UNDERSTAND AND
WORK WITH FAMILIES TO UNDERSTAND
HOW THAT CHILD'S RECOVERING AND
DEVELOPING AGAIN AT THE SAME
TIME.
I MENTIONED THAT YOU CAN USE
RTMS REPETITIVELY, MULTIPLE
STIMULATIONS O EXCITE OR
INHIBIT.
HERE IS A THIS IS LOOKING AT
ADULT RTMS STUDIES AND CAME UP
WITH THE CONCLUSION THAT THE
MAJORITY OF THE ARTICLES REPORT
THERE WERE POTENTIAL
IMPROVEMENTS IN MOTOR FUNCTION
AND ENCOURAGES MORE OF THESE
STUDIES TO ACTUALLY LOOK AT
RCTs AND THE OUTCOMES OF USING
RTMS.
IN OUR OWN LAB, WE'VE DONE AN
RTMS STUDY WITH CHILDREN WHO
HAVE EARLY BRAIN INJURY AND
RESULT IN CEREBRAL PALSY FUNDED
OBAMA SAM ULIS CHALLENGE GRANT
AND THERE WERE SIGNIFICANT
IMPROVEMENTS IN HAND CHILDREN
FOR CHILDREN WHO HAD THE REAL
RTMS.
THE KIDS WERE SAFE, THERE WERE
NO ADVERSE EVENTS.
AND ALTHOUGH IT WAS CHALLENGING
TO ENROLL, THERE WAS A VERY HIGH
RETENTION OF GOOD TOLERANCE OF
THE ACTIVITY.
I'LL SHOW YOU A VIDEO OF ONE OF
THE INDIVIDUALS WHO PARTICIPATED
IN THAT STUDY AND HER INITIAL
GOAL WAS TO PUT A PONYTAIL IN
HER HAIR BY HERSELF SO WHEN SHE
WENT OFF TO COLLEGE SHE COULD DO
IT WITHOUT HAVING SOMEONE ASSIST
HER AND IN HER COMMENT AT THE
END WAS, IT MIGHT NOT BE PRETTY
BUT I DID IT BY MYSELF.
LOOKING AT LONGITUDINAL OUTCOMES
AND WE DID IT AFTER THE STUDY
LOOKING AT TWO TO FOUR YEARS
AFTER AND FOUND NO SIGNIFICANT
DIFFERENCES IN TERMS OF OUTCOMES
AND NO ADVERSE EVENTS THAT WERE
A TYPICAL TO THE AGE RANGE IN
WHICH THESE INDIVIDUALS WERE.
IT'S HELPFUL TO SEE THIS WAS
SAFE STUDY AND FURTHER
LONGITUDINAL STUDIES NEEDED TO
BE DONE.
TRANCE CRANIAL DIRECTING CURRENT
STIM YOU LACE ALLOWS US TO
INFLUENCE WHAT IS HAPPENING WITH
BRAIN ACTIVITY.
IT'S PORTABLE AND IT HAS MUCH
LESS RISK FOR ADVERSE EVENTS AND
ADULT STUDIES HAVE BEEN DONE
FROM 14 ADULT PATIENTS COMBINING
TDCS WITH CONSTRAINT INDUCED
THERAPY AND FOUND ALTHOUGH THERE
WERE IMPROVEMENTS IN BOTH
GROUPS, THE GAINS WERE LARGER IN
THE ACTIVE TDCS STUDY AND WE DID
THE SAME WITH A NIH AND NINDS
KO1 STUDY LOOKING AT TDCS WITH
CONSTRAINT INDUCED THERAPY AND
THE CIRCUITRY, THE WEIGHT OF THE
BRAIN WAS DEVELOPING AND
RECOVERING AT THE SAME TIME
INFLUENCED HOW A CHILD RESPONDED
TO INTERVENTIONS AND THERE WERE
NO ADVERSE EVENTS AND IT WAS
VERY GOOD T TOLERANCE.
KATHLEEN FRIEL HAS LOOKED AT
ROBOTICS IN AN ADULT WITH
CEREBRAL PALSY WHO HAD 36
SESSIONS OF USING TDCS TO EXCITE
THE CORTEX COMBINED WITH AN HOUR
OF INTERACTIVE ROBOTIC TRAINING
AND FOUND IMPROVEMENTS NOT ONLY
IN TERMS OF THE ABILITY FOR THE
INDIVIDUAL TO MOVE WITH THE
ROBOT AND DRAW, BUT ALSO, IN
TERMS OF THEIR MOTOR MAP AND THE
EXPANSION OF INCREASING SIZE AND
EXCITE ABILITY AFTER THE
THERAPY.
THE LAST THING I'LL TALK ABOUT
IS THE VAGAL NERVE, WE'RE CARING
IN ADULT STROKE WITH VNS WITH
ROW HABITATION AND THROUGH THAT
ON THE PAR HE HAVE RAL LEVEL
THEY FOUND IN THIS STUDY THERE
WERE CLINICAL MEANINGFUL RATES
WERE DOUBLED WITH VNS
REHABILITATION AND 50% HAD A
RESPONSE AT DAY ONE POST THERAPY
SO THIS WAS ACTUALLY A STUDY
THAT RESULTED IN THE FDA
APPROVAL OF THIS TYPE OF THERAPY
IN AUGUST OF 2021 AND IT'S NOW
BEING USED.
IF YOU TRANSLATE THIS TO INFANTS
IN TERMS OF INFANTS CAN EARLY
BRAIN INJURIES, DOUGH JENKINS
AND HER DEEM HAVE DONE A STUDY
IN 14 INFANTS, 11 PREMATURE AND
THREE WITH -- THE GOAL WAS
ACTUALLY TO KEEP THE INFANTS
SAFE IF THEY USED VNS AND
INCREASE FEEDING VOLUMES SO THEY
CAN HAVE ADEQUATE WEIGHT GAIN TO
BE DISCHARGED WITHOUT SURGICAL
INTERVENTION AND G-TUBE.
THERE WERE NO ADVERSE EVENTS AND
EIGHT OF THE RECEIVED ADEQUATE
FEEDING VOLUMES WITHOUT THE
G-TUBE AND SIGNIFICANT INCREASES
IN FEEDING VOLUME RA
TRAJECTORIES SO THE STIMULATION
REALLY DID HAVE A CLINICAL
MEANINGFUL EFFECT.
SO HOW DOES THIS RELATE TO THE
STRATEGIC PLAN IN THE WORK THAT
I JUST BRIEFLY SHARED OVER
ADULTS AND PEDIATRICS IN
CORTICAL PLASTICITY?
WELL ONE IS WE TALKED ABOUT SOME
OF THE CRITICAL PERIODS OF BRAIN
AND MOTOR DEVELOPMENT AND
LOOKING ACROSS THE LIFESPAN OF
THOSE AND WE'VE CONSIDERED
NEURAL PLASTIC PROMOTING
INTERVENTIONS FROM THE OTHER
FIELDS SO THERE ARE DIFFERENT
WAYS TO ACTUALLY COMBINE
REHABILITATION WITH OUR NEURO
MODULATORY ALONE.
WE'VE CONSIDERED THE ENTIRE
LIFESPAN FOR LEVERAGING NEURO
PLASTICITY AND AS WELL AS
COMBINATION THERAPY SUCH AS NON
INVASIVE BRAIN STIMULATION AND
CONSTRAINT-INDUCED THERAPY FOR
OUR TARGETING OF DIFFERENT
PATHWAYS.
AND ALSO TRYING TO ACCELERATE IF
NOT ACTUALLY ACHIEVE A BENCH
SIDE APPROACH FOR TRANSLATIONAL
INTRA SELECTIONS THAT SOON IF
NOT HAVE NOT ALREADY BEEN
TARGETED SPECIFICALLY FOR
CEREBRAL PALSY.
SO THIS IS AN INDIVIDUAL WHO WAS
WORKING WITH US IN THE NICU AND
SHE'S TWO AND HER T-SHIRT SAYS
I'M THIS MANY WITH FINGERS UP.
THE CORTICAL PLASTICITY AND
RECOVERY TO UNDERSTAND HOW AS AN
INDIVIDUAL WITH EARLY PERINATAL
BRAIN INJURY OR LATER IN THEIR
LIVES, HOW IS THAT PLASTICITY
TRANSLATE FROM ADULT TO
PEDIATRIC POPULATIONS.
I WANT TO THANK MY ENTIRE TEAM
WHO DID THE MAJORITY OF THE WORK
THAT I JUST SHARED AND WHO I
HAVE THE GREAT PLEASURE OF
WORKING WITH BOTH MY COLLEAGUES
AS WELL.
ALL OF MY COLLEAGUES AS WELL.
SO, I THANK YOU VERY MUCH FOR
YOUR ATTENTION AND THE
OPPORTUNITY TO SHARE AND TO
LEARN MORE FROM YOU AS WELL.
>> THANK YOU, EVERYBODY.
ALL OF THE PRESENTATIONS TODAY
HAVE BEEN ABSOLUTELY FANTASTIC.
AND I WANT TO THANK ALL OF OUR
SPEAKERS FOR THEIR
PARTICIPATION.
SO, TODAY WE'VE ACTUALLY HEARD
PRESENTATIONS ABOUT THE NIH
CEREBRAL PALSY RESEARCH FUNDING
PORTFOLIO.
ONE OF THE THINGS THAT YOU SAW
WAS THAT THERE WAS A SUBSTANTIAL
INCREASE IN THE NUMBER OF
TRAINEES THAT ARE BEING FUNDED
BY NIH TO PERFORM CEREBRAL PALSY
RESEARCH.
SORT OF SEEDING THE FIELD FOR
NEXT GENERATIONS.
WE ALSO HEARD A WONDERFUL
PRESENTATION FROM Ms. ANDERSON
ABOUT WHAT IT'S LIKE TO LIVE
WITH CEREBRAL PALSY AND
PARTICIPATE IN AN NIH-FUNDED
CLINICAL RESEARCH ENTERPRISE.
WE ALSO HEARD ABOUT HOW NOVEL
ANIMAL MODELS CAN BE USED TO
INFORM UNDERSTANDING ABOUT
CEREBRAL PALSY FUNCTIONAL
DEFICITS, GENETICS AND ACTUALLY
AID IN THE DEVELOPMENT OF NEW
THERAPIES.
WE'VE HEARD ABOUT ADVANCES IN
USING NEUROIMAGING POTENTIALLY
TO DIAGNOSE CP EARLIER AND WE
ALSO HEARD ABOUT IMPORTANT, HOW
IMPORTANT CENTURY MOTOR FEEDBACK
IS FOR IMPROVING LIMB FUNCTION
AND HOW NEURO PLASTICITY IN
DIFFERENT FORMS OF NEURO
MODULATION CAN BE LEVERAGED TO
ENHANCE CEREBRAL PALSY RECOVERY.
SO, WE'VE COVERED A PRETTY WIDE
PIECE OF LANDSCAPE HERE DURING
THE COURSE OF TODAY.
AND ALL SIX OF THESE
PRESENTATIONS THAT WE'VE HEARD
HAVE REALLY KIND OF EMPHASIZED
HOW THESE ELEMENTS FEED INTO THE
STRATEGIC PLAN THAT WE PUBLISHED
IN 2017.
SO, WHAT I WANT TO DO AT THIS
PARTICULAR POINT, IS KIND OF
TAKE A STEP BACK AND PULL UP
SOME OF THE QUESTIONS FROM OUR
QUESTION AND ANSWER AUDIENCE.
THAT WERE ASKED VIA THE QUESTION
AND ANSWER PERIOD.
IF ALL OF OUR SPEAKERS FROM
TODAY, ALL SIX, CAN ACTUALLY
TURN ON THEIR CAMERAS, AND I
WILL ASK SOME QUESTIONS AND YOU
CAN ANSWER THEM DIRECTLY IF YOU
DON'T MIND.
SO I'M GOING TO ASK MY
COLLEAGUE, TO ALSO HELP ME
IDENTIFY SOME OF THESE QUESTIONS
GOING FORWARD.
SO PLEASE FEEL FREE TO CHIME IN
IF I MISS ANYTHING.
SO, LET ME START FIRST BY ASKING
A COUPLE OF QUESTIONS TO BHOOMA
SINCE SHE WAS OUR KICK-OFF
SPEAKER FOR THE SIX
PRESENTATIONS.
ONE OF THE QUESTIONS WAS, IS
MOVEMENT CAPTURE IN YOUR MOUSE
MODELS ALSO DONE WITH WEIGHT
BEARING AND DOES IT QUANTIFY OR
DOES IT RELATE TO THE CLINICAL
SCALE THAT YOU ACTUALLY USE?
>> YEAH, THANK YOU FOR THAT
QUESTION.
THANK YOU FOR ALL OF THESE
TALKS.
IT'S GREAT TO LEARN FROM ALL OF
YOU, LEARN FROM EACH OTHER.
SO, I'M EXCITED TO BE HERE.
THE ANSWER TO THAT QUESTION, SO,
WE LOOKED AT SPECIFICALLY FEAR
TURES OF DYSTONIA THAT WE
DERIVED DIRECTLY FROM THE
CLINIC.
WE DO OUR BEST TO LOOK FOR
CLINICALLY RELEVANT FEATURES OF
THE MOTOR PHENOTYPES WE STUDY
AND DYSTONIA IS MY.
IT'S QUANTIFY DYSTONIA PEOPLE SO
WE CAN TRANSLATE THAT TO MICE IN
A CLINICALLY RELEVANT WAY.
WE LOOK AT MICE SUSPENSION
BECAUSE THAT IS THE WAY DYSTONIA
HAS BEEN CLASSIFIED IN MICE AND
WE ALSO LOOK AT IT DURING
TREADMILL WALKING SO DURING
WEIGHT-BEARING, DURING GAIT IN
MICE AND WE DO THE RANGE OF
CONVENTIONAL WE USE TO ASSESS
MICE AS WELL.
WE WANT TO BE CAREFUL THAT IT'S
VERY DIFFICULT TO ASSESS WHAT A
FUNCTIONALLY RELEVANT GOAL IS
FOR A MOUSE AND TO HAVE THAT BE
TRANSLATIONAL TO PEOPLE.
SO, WE ALSO KNOW THAT OPEN FIELD
WALKING IN MICE THAT YOU TAKE A
LOT OF BRAIN INJURIES TO
ACTUALLY GET ANY SORT OF EFFECT.
SO, WE WANT TO BE VERY CAREFUL
ABOUT USING CLINICALLY RELEVANT
STRATEGIES TO ASSESS MOTOR
OUTCOMES IN MICE BUT ALSO BE
REALISTIC ABOUT WHAT FUNCTION
REALLY MEANS WHEN YOU ARE
TALKING ABOUT A MOUSE COMPARED A
PERSON.
>> GREAT, THANK YOU.
WONDERFUL ANSWER.
SO, ANOTHER QUESTION FOR YOU
IS -- DO YOU FIND OR BELIEVE
THAT WHITE MATTER DEVELOPMENT IS
EFFECTED IN YOUR HYPOXY MODEL?
AND THAT IT MIGHT CONTRIBUTE TO
THE DYSTONIA AND OTHER
PHENOTYPES THAT YOU OBSERVED?
>> YES.
SO, WHITE MATTER INJURIES
ACTUALLY PRETTY LIMITED IN OUR
MODEL IN TERMS OF NEURONAL LOSS
AND LONGSTANDING GLEOSIS AND
SIZE MEASUREMENTS SO THERE'S NO
DIFFERENCE IN CORTICAL ROI SIZE
AND THERE'S NO SIGNIFICANCE
DIFFERENCE IN THE NUMBER.
SO, COULD THERE BE SOME DEGREE
OF WHITE MATTER INJURIES THAT WE
HAVEN'T QUANTIFIED USING KIND OF
PATHOLOGIC METHODS?
SURE.
IS IT A STILL A SIGNIFICANT
CONTRIBUTE OR TO MOTOR
DYSFUNCTION, EVEN BEYOND THE
SOURCE OF GROSS MEASURES?
YES IT COULD.
I THINK MAYBE PERHAPS PART OF
THE HIDDEN SUBJECTS IN THAT
QUESTION IS, HOW MUCH ARE WE
DIFFERENTIATING BETWEEN DYSTONIA
PLASTICITY IN THESE MODELS AND
THERE ARE A LOT OF DIFFERENT EMG
STUDIES THAT WE'VE DONE AND WAYS
WE'VE DEVELOPED IT AND WE'VE
APPLIED TO THE MICE WHICH I'M
HAPPY TO TALK MORE ABOUT, I CAN
DO ANOTHER TALK ON THAT.
WE DO TROY AND DIFFERENTIATE
BETWEEN THOSE FEATURES TOO.
SHORT ANSWER IS IS THERE A LOT
OF WHITE MATTER INJURY IN
THISSED MONTHEL, NO.
AND THAT'S CONSISTENT WITH
PEOPLE OBSERVED PREVIOUSLY WITH
MODELS LIKE THIS AS WELL.
>> Jim: GREAT.
THANK YOU.
SO, THE NEXT QUESTION IS FOR
Dr. KRUER.
AND HAS ANYONE STUDIED THE
INCIDENTS OF CP IN CHILDREN WITH
A PARENT WITH CEREBRAL PALSY?
IS IT HIGHER THAN TYPICAL?
IS STUDYING KIDS OF PARENTS WITH
CEREBRAL PALSY LIKELY TO MAKE AN
IMPACT?
>> YEAH, ALSO THANK YOU FOR THE
OPPORTUNITY TO BE HERE WITH ALL
OF YOU TODAY.
IT'S BEEN AN EXCITING WORKSHOP.
I'M LOOKING FORWARD TO THE
SECOND HALF.
AS FAR AS THE QUESTION GOES, THE
SHORT ANSWER IS YES, THAT HAS
BEEN LOOKED AT IN PARTICULAR
THERE WAS A SCANDINAVIAN
POPULATION-BASED STUDY THAT WAS
PUBLISHED SEVEN OR EIGHT YEARS
AGO AT THIS POINT IN TIME THAT
LOOKED AT FAMILIAL OCCURRENCE OF
CEREBRAL PALSY.
ALTHOUGH WE TYPICALLY THINK
ABOUT CEREBRAL PALSY AS BEING A
SPORADIC OCCURRENCE, OVER TIME
WE'RE RECOGNIZING THERE'S A
DIVERSE SET OF GENETIC CHANGES
THAT CAN LEAD TO CEREBRAL PALSY
AND AS I MENTIONED, AND OTHERS
HAVE MENTIONED THERE ARE BOTH
GENETIC AND OTHER FACTORS THAT
WILL INTERACTS TO LEAD TO
CEREBRAL PALSY.
SO, WE DO KNOW FOR EXAMPLE THAT
IN OFFSPRING OF PARENTS THAT
HAVE DIAGNOSIS OF CEREBRAL PALSY
THE INCIDENTS IN THEIR CHILDREN
IS HIGHER AND AT LEAST SOME OF
THAT IS THOUGHT TO BE DUE TO
MUTATIONS THAT CAN POTENTIALLY
CROSS GENERATIONAL LINES AND BE
INHERITED, FOR EXAMPLE, IN A
DOMINANT MATTER.
I THINK OVER ALL, THIS SPEAKS
THOUGH TO THE FACT THAT WE'RE
JUST SCRATCHING THE SURFACE
WHERE IT COMES TO THE GENETICS
OF CEREBRAL PALSY AND THERE'S
STILL A GREAT DEAL TO LEARN.
I THINK THAT AS I HIGHLIGHTED
BRIEFLY IN MY TALK, THERE'S
GREAT OPPORTUNITIES TO REALLY
DIVERSIFY THE STUDIES AND
CONSIDER ALL TYPES 6 INHERIT
DIFFERENT FAMILY STRUCTURES AND
DIFFERENT ETH NICE T ETHNICITIEI
THINK WE'LL LEARN A LOT.
>> Jim: THANK YOU, MICHAEL.
THAT WAS VERY GOOD.
LET ME ASK Dr. PARIKH A
QUESTION.
LET ME SEE IF I CAN FIND IT
HERE.
SORRY.
OOPS.
>> I THINK IT'S THE ONE FROM
HEATHER HANCOCK.
>> I'M HAPPY TO READ IT.
>> Jim: GREAT.
THANK YOU.
>> I ALSO WANT TO ECHO THE
COMMENTS ABOUT HOW WONDERFUL
THIS IS.
THANK YOU SO MUCH TO ALL THE
ORGANIZERS AND ALL THE SPEAKERS,
REALLY.
FOR THE EDUCATIONAL AND EDUCATI.
IF THE LEASHANCE ARE VISIBLE BUT
AS THE BABIES BECOME ADULTS THEY
DON'T SHOW ON SCANS.
WHY DOES THIS HAPPEN?
>> IT'S A GREAT QUESTION.
IT HAPPENS IN BABIES TOO SO OUR
PREMATURE BABIES IF WE IMAGE
THEM WEEKLY WILL SOMETIMES SEE
THESE LESIONS DISAPPEAR,
ESPECIALLY CYSTIC SO SOME
RECOMMEND THAT THESE PRE TERM
BABIES ARE IMAGED EVERY WEEK.
HOWEVER, IF YOU KNOW WHAT YOU
ARE LOOKING FOR, YOU CAN STILL
FINDS THOSE THINGS.
SO FOR EXAMPLE, IN PREEMIES AT
TERMS, THEY WILL OFTEN TIMES
HAVE BIGGER VENTRICLES SO
INLARGEMENT IS THE PVL.
AND IN ADULTS, LIKELY, WHAT
WE'RE SEEING IS THE BRAIN SHA
RINKS SO THE WHITE MATTER SO YOU
WILL SEE SCARRING AND THAT WHITE
MATTER VOLUME WILL GET SMALLER.
THE VENTRICLES WILL COMPENSATE
AND GET BIGGER.
IT'S MORE SUBTLE AND HARD TO
DETECT SO UNLESS YOU KNOW WHAT
YOU ARE LOOKING FOR AND YOU ARE
ABLE TO USE A RIGHT SEQUENCES,
MRI SEQUENCE TO DETECT THOSE
INJURIES, I WOULD SAY CERTAINLY
HAVING LONGITUDINAL IMAGING WILL
MAKE IT A LITTLE BIT MORE
SENSITIVE TO PICK UP THOSE
ABNORMALITIES.
OR PICKING THE IMAGES IN THE
SENSITIVE PERIODS OF DEVELOPMENT
WHEN MOST THESE INSULTS OCCUR
WILL ALLOW YOU TO DETECT AND PRO
DICTIONARY OUTCOMES MUCH MORE
READILY AND ALSO, I THINK USING
MORE ADVANCE MODALITY SUCH AS
DIFFUSION IMAGING WHERE YOU CAN
ACTUALLY LOOK AT THESE SENSORY
MOTOR TRACKS, I THINK WE WOULD
ALLOW YOU TO QUANTIFY THE INJURY
BETTER WHEN THESE OBVIOUSLY
LESIONS DISAPPEAR SO THERE ARE
OTHER WAYS TO GET AROUND THIS
CONUNDRUM.
>> Jim: SO, LET ME ASK ANOTHER
QUESTION.
AND THAT IS, YOU MENTIONED
DIFFUSION MRI.
HOW EARLY DO YOU THINK THAT CAN
ACTUALLY REALISTICALLY BE
DEPLOYED IN NEONATES?
>> YEAH, THAT'S ANOTHER
FANTASTIC QUESTION.
WE'VE DONE SOME IMAGING EARLIER
IN BABIES AND OTHER GROUPS SUCH
AS FROM AUSTRALIA AND THE U.S.
AND THE U.K. AND PEOPLE ARE
TRYING TO GET EARLIER AND
EARLIER WITH THEIR DIAGNOSIS
BECAUSE OF COURSE INTERVENTION,
EARLIER INTERVENTION COULD MEAN
PREVENTION OF CP ALL TOGETHER OR
AT A MINIMUM REDUCING A SEVERITY
OF CEREBRAL PALSY.
SO THERE'S SOME REALLY GOOD DATA
FROM 32 WEEKS AND INCREASINGLY,
THE DATA IS COMING OUT 6 OUT OF
AUSTRALIA NOW THAT YOU COULD
DETECT INJURY AT 32 WEEKS AS
WELL.
I THINK SOME OF THESE BABIES
THAT ARE UNDER OUR CARE,
SUFFERING INJURY EVEN BEYOND 32
WEEKS SO I THINK THE OVER ALL
SENSITIVITY WILL BE HIGHER AT 40
WEEKS BUT THEN YOU LOSE THOSE
EIGHT WEEKS OF MATURATION AND
NEURO PLASTICITY SO IF YOU ARE
REALLY WANTING TO GET IN THERE
EARLY, SOME OF THESE BABIES WILL
SHOW THE ABNORMALITIES BEFORE 32
WEEKS PERHAPS.
BUT AT LEAST BY 32 WEEKS.
MANY.
>> Jim: GREAT.
THANK YOU.
SO, LET ME BACK UP.
RACHEL, LET ME ASK YOU A
QUESTION IF I CAN.
ARE THERE WAYS THAT YOU CAN
SUGGEST THAT RESEARCHERS CONNECT
WITH STAKEHOLDERS AND ADVOCATES
ACROSS THE COUNTRY?
IS THERE A PLACE WHERE
RESEARCHERS CAN ACTUALLY CONNECT
WITH STAKEHOLDERS AND EXPRESS
THEIR WILLINGNESS TO BE PART OF
RESEARCH TEAMS?
>> YEAH, ABSOLUTELY.
AND SON JUST TO PROMOTE THE
CEREBRAL PALSY FOUNDATION BUT
OBVIOUSLY IT'S A HUGE PRIORITY
AREA.
TO MAKE SURE RESEARCHERS CAN
COME WITH PROJECTS IN THE LAST
COUPLE OF YEARS AND PURELY FOR
THAT PURPOSE AND OBVIOUSLY THERE
WAS A LITTLE BIT OF WORK ON OUR
COLLABORATIONS TOGETHER BOTH
THROUGH THE EARLY DETECTION
NETWORK AND OTHER PIECES.
THE EXCITING OPPORTUNITY HERE
THOUGH IS THAT THE COMMUNITY
WANTS TO BE INVOLVED.
WE HAVE A VERY ENGAGE COMMUNITY
BOTH INDIVIDUALS WITH CEREBRAL
PALSY AND THEIR FAMILIES AND
THEY DO WANT TO BE INVOLVED SO
WE HIGHLY RECOMMEND FOR
RESEARCHERS TO REACH OUT TO
STAKEHOLDER GROUPS WHETHER IT'S
THE CEREBRAL PALSY FOUNDATION OR
WHETHER IT'S CEREBRAL PALSY
RESEARCH NETWORK.
WE NOW HAVE THE INFRASTRUCTURE
IN PLACE TO BE ABLE TO HELP TO
RECRUIT TO THESE STUDIES AND THE
OTHER PIECES TO THINK ABOUT IS
WHAT DOES THE METH MYTHOLOGY LOK
LIKE SO WE CAN ENSURE THAT BOTH
THE STUDY ITSELF IS WHAT THE
COMMUNITY WANTS BUT ALSO THE
OUTCOME MEASURES AS WELL BUT
YEAH, I WOULD HIGHLY RECOMMEND
TO REACH OUT TO THE FOUNDATION
OR REACH OUT TO SEVERAL RESEARCH
NETWORKS AND WE ARE BOTH HIGHLY
ENGAGE IN THOSE ACTIVITIES.
>> GREAT.
THANK YOU.
I KNOW THERE WAS A FAIR NUMBER
OF COMMENTS IN THE QUESTION AND
ANSWER ABOUT HOW PEOPLE CAN GET
INVOLVED SO I THINK THAT THAT
WAS GREAT.
>> AND FOR THE COMMUNITY ITSELF,
WE HAVE A PAGE OR CEREBRAL PALSY
RESOURCE.
IT'S SPECIFICALLY FOR CLINICAL
TRIALS AND RECRUITMENT AND IT
HAS BOTH STUDIES BROKEN DOWN BY
AGE AS WELL AS GEOGRAPHICAL
REGIONS SO FOR ANY OF THE
COMMUNITY MEMBERS WHO WANT TO GO
HAVE A LOOK AT THAT.
IT HAS IT AUTOM ALL BROKE UNDOW.
>> Jim: TERRIFIC, THANK YOU.
KATHY, A QUICK QUESTION FOR YOU.
YOU TALKED A LOT ABOUT SEROTONIN
AND VOLUME TRANSMISSION AND ITS
DEVELOPMENT, AND POTENTIAL USE
AS A THERAPEUTIC.
SEROTONIN IS PRETTY WIDELY
EXPRESSED THROUGHOUT THE BRAIN
AND THE GUT AND A LOT OF OTHER
PLACE, HOW DO YOU THINK THAT YOU
COULD TARGET AN INTERVENTION
SPECIFICALLY ENOUGH IS THAT IT
WOULD NOT HAVE A LOT OF SIDE
EFFECTS AND MIGHT BE BENEFICIAL
IN CP?
>> IT'S A GREAT QUESTION.
AND THE SHORT ANSWER IS THAT WE
HAVE A LOT OF WORK YET TO DO IN
ORDER TO BE ABLE TO ANSWER THAT
AND HOPEFULLY BY TARGETING THE
SPECIFIC RECEPTORS SUBTYPE, AND
THE SPECIFIC TIMING AT WHICH IT
WOULD BE EFFECTIVE AT REDUCING
HYPER TONIA OR SASS SIS TEE, IT
COULD HELP TARGET IT TO THE
LOCATION AS WELL.
>> POTENTIALLY THE RECEPTORS IS
EXPRESSED IN OTHER AREAS BESIDES
THE SPINAL CORD.
THERE ARE 5HT2A RE SCEPTER AND
DEVELOPING MUSCLE FIBERS AND
SATELLITE CELLS FOR EXAMPLE.
FIRST OF ALL, THE DEVELOPING
MUSCLES MAY ALSO BE EXPOSED TO
INCREASE SEROTONIN THAT HASN'T
BEEN DEMONSTRATED WHETHER THEY
HAVE OR NOT.
I AM INTERESTED IN LOOKING MORE
BROADLY AT THE DEVELOPING MOTOR
UNIT AND TO TRY TO DISCERN
WHETHER IT'S NEEDED IN THE
CENTRAL NERVOUS SYSTEM MORE
GLOBALLY AND THAT'S ANOTHER KEY
QUESTION.
IT'S POSSIBLE THAT IT COULD BE
APPLIED ONCE IF IT'S ONLY NEEDED
IN THE CENTRAL NERVOUS SYSTEM
BUT THAT'S SEVERAL STEPS DOWN
THE ROAD AND I DON'T KNOW THOSE
ANSWERS YET.
>> Jim: SO, BETWEEN YOU AND
BERNADETTE AND ACTUALLY NATALIE
ALSO, IS THERE ANY INDICATION
THAT NEURO MODULATION, OR THE
SENSORY MOTOR STIMULATION THAT
NATALIE WAS TALKING ABOUT, MIGHT
ACTUALLY IMPACT ON THE
DEVELOPMENT OF THE SYSTEM.
IS THAT ONE WAY THAT THESE
PARTICULAR INTERVENTIONS COULD
BE WORKING?
>> I WOULD GUESS, ABSOLUTELY
YES.
I'VE HAD SOME INTERESTING
CONVERSATIONS WITH NATALIE ABOUT
THE SAME TOPIC AND I ABSOLUTELY
THINK SO.
I THINK THAT THE -- IT'S BEEN
DEMONSTRATED THAT RECEPTORS HAVE
A LOT OF IMPORTANCE IN SENSORY
AND PAIN PROCESSING PATHWAYS AND
THESE ARE EXTREMELY IMPORTANT IN
CEREBRAL PALSY.
>> I WOULD SAY ALSO, ON
PIGGYBACKING ON THAT, WE CAN
MEASURE CENTRAL AND PERIPHERAL
TIMES AND START TO UNDERSTAND
FURTHER WHAT IS HAPPENING FROM A
NEUROPHYSIOLOGICAL AND NEURO AN
ATOMIC PERSPECTIVE SO IT'S A
GREAT OPPORTUNITY AND TO USE
MODELING AS WELL TO DO THAT.
>> I AGREE.
THE OTHER THING IS THAT SOME OF
THESE SYSTEMS AFFECT THE LARGER
PICTURE, RIGHT.
IF YOU THINK ABOUT THE
INTERNATIONAL CLASSIFICATION OF
FUNCTION, YOU ARE ALSO TALKING
ABOUT SEROTONINS' IMPACT NOT
JUST FOR SENSORY MOTOR PROCESSES
IN CEREBRAL PALSY BUT ALSO IN
LEARNING ITSELF AND HOW EMOTION
AND CONNECTION ALSO FOSTER
LEARNING.
SO IT'S REALLY COMPLEX AND I
ACTUALLY THINK THAT THIS IS
CRITICAL WORK IN UNDERSTANDING
MORE THAN SIMPLY META SENSORY
AND MOTOR PROCESSES BUT
EVERYTHING ELSE THAT GOES WITH
FUNCTION AND CP.
>> TAKING OFF FROM WHAT YOU JUST
SAID AND THINKING ABOUT WHAT
MICHAEL SAID ABOUT THE N OF 1,
CLINICAL TRIALS AND THEIR
IMPORTANCE, ARE SOME OF THE
NEURO MODULATORY AND SENSORY
MOTOR INTERVENTIONS POTENTIALLY
USEFUL IN THE N OF 1 CONTEXT AND
IS THERE A WAY TO TIE THE
GENETICS TOGETHER WITH SOME OF
THE NEURO MODULATION ATTEMPTS?
>> YES.
I'M GOING TO SAY I'M GOING TO
SPEAK FOR AUTOMA ALL OF US ON TL
AND THAT --
>> Jim: O. WELL, THAT WAS KIND
OF AN OPEN-ENDED QUESTION, I
GUESS.
SO, BERNADETTE, LET ME ASK YOU
ANOTHER QUESTION.
THANK YOU FOR TAKING US THROUGH
ALL THE NEURO MODULATORY
STRATEGIES LIKE DCS AND TM S AND
VAGAL NERVE STIMULATION BUT THEY
HAVE RATHER BREWED DIFFUSE DIFF-
IS THERE A POSSIBILITY OF THE
DEVELOPING BRAIN AND MAYBE EVEN
MALL ADAPTIVE EFFECTS.
>> ABSOLUTELY.
WHAT I DIDN'T SPEND THE TIME ON
IS OUR MODELING.
IT'S TOO GENERAL AND TOO DIFFUSE
IN TERMS OF SPECIFIC TARGETED
ACTIVITIES SO, IT'S AN AREA THAT
WE NEED TO IMPROVE UPON AND WHEN
YOU ARE ASKING THAT QUESTION, OF
Dr. QUINLAN AND Dr. MAITRE,
I WAS THINKING, HOW DO WE BECOME
MORE SPECIFIC IN OUR TARGETS.
JUST AS THAT IS WHY I MENTIONED
THE MALL ADAPTIVE PLASTICITY AND
RESEARCH AT THIS LEVEL TAKES A
LOT OF RIGGER AND IT SHOULD AND
WE SHOULD BE STEWARDS FOR THE
SAFETY FOR THE INDIVIDUALS WHO
WE SERVE AND SO IT'S REALLY A
GREAT QUESTION IN TERMS OF
CONTINUING THAT LINE AND IT'S
REALLY IMPORTANT AND I LOVED
THAT COMMENT BECAUSE LOOKING AT
EACH ONE OF THOSE INDIVIDUAL
CASES ALLOWS US, IT'S 100% MORE
THAN WE HAD WHEN WE DIDN'T HAVE
ANYONE SO WHEN WE PUT IT
TOGETHER IT TELLS A STORY OF
SAFETY, FEASIBILITY AND THEN
EFFICACY WHICH IS REALLY
IMPORTANT.
>> Jim: THANK YOU.
SO, MICHAEL, LET ME COME BACK
AND ASK YOU ANOTHER QUESTION.
ONE OF THE THINGS THAT WE KNOW
ABOUT CEREBRAL PALSY IS IT'S
VERY, VERY HETEROGENEOUS
DISORDER AND I'M CURIOUS IN YOUR
STUDIES, HOW DO YOU USE THAT TO
YOUR ADVANTAGE?
DO YOU HAVE TO DO REALLY SOME
VERY STRONG PHENOTYPING TO BE
ABLE TO MAKE THE GENETICS WORK
OR CAN YOU USE THE HETEROGENEITY
OF CEREBRAL PALSY AS A WAY TO
EXPAND SOME OF YOUR GENOMICS?
>> THANK YOU FOR THE QUESTION.
I THINK THAT IT GOES BOTH WAYS.
SO THAT THE LIMITED CLINICAL
INFORMATION WE CAN STILL
SOMETIMES DERIVE SOME IMPORTANT
FINDINGS FROM THE GENETICS.
I'M OFTEN FOND OF SAYING THAT
THE GENOMICS ARE REALLY ONLY ONE
SIDE OF THE COIN AND IF WE
QUOTE-UNQUOTE DISCOVER A NEW
GENE,
WHAT DID WE JUST DISCOVER?
THE CLINICAL PHENOTYPES AND I
MEAN THAT VERY BROADLY.
NOT ONLY LOOKING AT MOVEMENT
DISORDERS BUT LOOKING AT NEURO
AND PHYSIOLOGY AND NEUROIMAGING
AND LOOKING AT INDIVIDUALS WITH
CEREBRAL PALSY AT A DEEP LEVEL,
I THINK REPRESENTS A TREMENDOUS
OPPORTUNITY BECAUSE AS WE ALL
KNOW, THERE IS A LOT OF
VARIABILITY IN TERMS OF THE
POPULATION OF PEOPLE LIVING WITH
CEREBRAL PALSY.
OVER TIME, WE ACTUALLY HAVE A
GREAT OPPORTUNITY AT THIS POINT
AND OVER TIME, WE'RE GOING TO BE
ABLE TO DO MORE KIND OF
PRECISION GENOMICS AND WE'LL
LOOK AT MORE DEEPLY INTO THE
CHARACTERISTICS OF AN INDIVIDUAL
CEREBRAL PALSY.
WE'LL BE ABLE TO DEFINE THAT AT
MULTIPLE LEVELS AND NOT JUST
WHAT WE SEE CLINICALLY, BUT WHAT
IS HAPPENING IN THE BRAIN AT A
STRUCTURAL LEVEL AND A
FUNCTIONAL LEVEL, DOWN TO THE
SPINAL CORD.
ALL THE OF THE THINGS THAT
YOU'VE HEARD ABOUT THIS MORNING,
I THINK REALLY CAN BE INTEGRATED
AND I THINK GENOMICS IS ONE TOOL
TO HELP TO DO THAT BUT MY HOPE
IS THAT WITH THE APPLICATION OF
MORE AND MORE PRECISE FEN OWE
TYPING IT WILL DRIVE OUTCOMES
RESEARCH OVER TIME AND IT WILL
BE ABLE TO SOMETIMES -- IF YOU
LOOK AT THREE INDIVIDUALS AND
ONE RESPONDS TO INTERSECTION AND
ONE RESPONDS NOT AT ALL AND ONE
RESPONDS IN THE MIDDLE, WELL THE
NET OF THAT IS REALLY NO
DIFFERENCE FROM A CONTROL GROUP.
PERHAPS, THERE MIGHT BE
DIFFERENCES IN TRYING TO LOOK AT
INDO PHENOTYPES OR SPECIFIC
CLINICAL DIFFERENCES THAT MIGHT
DRIVE DIFFERENCES IN RESPONSE.
>> Jim: GREAT.
THANK YOU.
SO, NATALIE, LET ME COME BACK TO
YOU WITH A FOLLOW-UP QUESTION.
IF I CAN.
AND IN YOUR APPLES' STUDY, YOU
TALKED ABOUT RECRUITING A VERY
DIVERSE SUBJECT POPULATION.
COULD YOU SHARE WITH US LITTLE
BIT MORE ABOUT YOUR STRATEGIES
TO ENHANCE DIVERSITY AND THE WAY
THAT YOU'VE RECRUITED FOLKS INTO
YOUR STUDY?
>> SURE, WHEN I FIRST STARTED,
AND IT PLAYS INTO EVERYTHING
OTHER PEOPLE HAVE TALKED ABOUT,
RIGHT.
YOU ARE TALKING ABOUT GENETIC
MAKE UP, ABOUT GENOMICS BUT IF
YOU ARE GOING TO GET RESULTS
THAT ARE GOING TO MATTER, YOU
NEED TO HAVE A WIDE DIVERSITY OF
PATIENTS.
SO IT REALLY TIES IN WELL TO
THAT.
SO, THE NIH HAS ON MANY OF THE
APPLICATIONS SOMETHING THAT'S
CALLED PDPE, I DON'T KNOW IF YOU
HAVE HEARD ABOUT IT.
SO A PLAN FOR ENHANCING DIVERSE
PERSPECTIVES AND RESEARCH AND
ANYWAY, WE TOOK IT PRETTY
SERIOUSLY.
AND ONE OF THE WAYS WE FIRST
ENHANCED DIVERSITY IS BY
ASSESSING BARRIERS AND FORGIVE
ME ONE SECOND.
WHAT ARE THE SOCIAL DETERMINANTS
OF HEALTH THAT COULD BE PLAYING
INTO NOT JUST PEOPLE'S RESPONSES
TO HAVING A CHILD WITH CEREBRAL
PALSY OR HIGH -RISK FOR CEREBRAL
PALSY BECAUSE WE START, YOU
KNOW, THERE'S A QUESTION ABOUT
STROKE AND WE START YOUNGER WHEN
THEY'RE HIGH-RISK.
WHAT ARE THE THINGS THAT PLAY
INTO THE DEVELOPMENT OF THE
CONDITIONS TO THEIR ACCESS TO
HEALTHCARE AND ALSO TO THEIR
ACCESS TO RESEARCH.
SO WHEN WE FIGURE OUT -- IT'S
DIFFERENT FOR EVERYONE, RIGHT.
IF YOU DON'T SPEND THE TIME,
ASSESSING IT, WHAT ARE THESE
SOCIAL -- AND IT'S PSYCHOSOCIAL
DETERMINANTS OF HEALTH.
WE ASSESS EVERYTHING FROM ACES
TO WHAT ARE THE IMPACT OF POST
TRAUMATIC STRESS DISORDER ON
THEIR FAMILY AND THINGS LIKE
THAT.
SO THAT WHEN THEY DO COME INTO
RESEARCH, WE KNOW WHERE THEY'RE
COMING FROM AND WE CAN MEET
THEM.
WE ALSO DESIGN OUR RESEARCH
BASED ON WHAT OUR STAKEHOLDERS
SAY THEY WANT.
AND THAT IS WHY IT WORKS, RIGHT.
WE GET MORE BUY-INTO TO OUR
RESEARCH BECAUSE PARENTS HELP
DESIGN EVERYTHING FROM THE
DESIGN OF THE TRIAL TO THE
INTERVENTIONS TO THE OUTCOMES
AND SO THEY FEEL LIKE THEY HAVE
A BUY IN INTO THE RESEARCH.
AND THEN THE LAST THING IS YOU
KNOW, IN ADDITION TO RESEARCH
THAT MATTERS AND THAT THEY CAN
DO, WE MAKE THE ENVIRONMENT AS
CONDUCIVE TO MEETING THEM AS WE
CAN.
SO, ALL THE RESEARCHERS THAT ARE
HERE AND ALSO TOMORROW, HAVE
LEVERAGED ALL THESE STRATEGIES,
RIGHT.
I'M NOT TEACHING ANYONE
ANYTHING.
WE HAVE SETTINGS IN WHICH
NURSING MOTHERS CAN BE BECAUSE
THEY'RE NURSING ROOMS, CHANGING
TABLES, THERE ARE KITCHENS,
THERE ARE ALL THESE THINGS THAT
MAKE REAL LIFE POSSIBLE AT THE
SAME TIME AS YOU DO RESEARCH.
AND WE ALSO HAVE PEOPLE WHO ARE
SPECIALIZED.
WHO MAKE SURE THAT WE'RE NOT
JUST CULTURALLY AWARE BUT WE'RE
CULTURALLY COMPETENT.
SO THAT WHEN WE HAVE THESE
FAMILIES, WE MAKE THEM FEEL
VALUED IN THE WAY THAT MATTERS
TO THEM.
AND I MEAN, WE GET PLENTY OF
HELP HONESTLY, YOU'VE HEARD ME
TALK ABOUT MY PARTNERSHIP WITH
THE CP FOUNDATION.
I'VE HAD TO LEARN A LOT ABOUT
WHAT DISABILITY IS BEYOND WHAT I
THOUGHT I COULD.
>> Jim: RACHEL.
DO YOU WANT TO CHIME IN ON THAT
ALSO?
>> YEAH, I THINK IT'S REALLY
IMPORTANT FROM THE STRATEGY FROM
THE BEGINNING AND THIS IS THE
PAY WHERE STAKEHOLDER
DEVELOPMENT AND STAKEHOLDER
COMMUNITY PARTICIPATION WHEN YOU
THINK ABOUT THE METHODOLOGY OF
THE STUDIES AND THINKING ABOUT
THE DESIGN AND IS IMPORTANT SO
ALL PEOPLE CAN PARTICIPATE,
RIGHT.
SOMETIMES WE CAN GET STUCK IN
GOING OR WE WANT TO DESIGN THE
PERFECT STUDY BUT THE PERFECT
STUDY MAY NOT BE APPLICABLE TO
THE COMMUNITY OR IT MAY NOT BE
EITHER WAY, TRANSLATABLE TO REAL
LIFE, RIGHT.
SO I THINK THESE PIECES AND
HAVING STAKEHOLDER INVOLVEMENT
NOT JUST AS ACTIVE PARTICIPANTS
IN THE STUDY BUT FROM THE
BEGINNING IS REALLY CHANGING THE
LANDS SCAPE AS TO HAVING SUCCESS
IN THESE PROJECTS.
>> Jim: AND SO, IN THAT
PARTICULAR CONTEXT, IF YOU'VE
GOT A SUBJECT FAMILY, A SUBJECT
AND THEIR FAMILY THAT'S ENGAGE
IN A STUDY, NATALIE, REACHEL AND
BERNADETTE, HOW DO YOU GET THE
RESEARCH BACK TO THE FAMILY AND
HOW DO THEY RESPOND TO THAT?
>> GREAT QUESTION, WE'VE LEARNED
A LOT AND WORKING WITH RACHEL
TOO AND WE TRANSLATE WE SEND
THEM TO THE FAMILY AND THE OTHER
FIRE DEPARTFIRE DEPARTPH.D, LETN
LANGUAGE INTERPRETATION THERE AS
WELL SO THAT'S ONE OF THE
EXAMPLES BUT HAVING THOSE
MEETINGS THE STAKEHOLDER
MEETINGS AFTER THE RESEARCH IS
IMPORTANT AS BEFORE THE RESEARCH
AND AS WELL.
>> THE ONE THING I LEARNED AND
JUST TO BE CLEAR, I DON'T
CONDONE THE USE OF SOCIAL MEDIA
AND MY CHILDREN DON'T HAVE
SOCIAL MEDIA HOWEVER THIS IS
WHERE WE NEED TO MEET OUR
STAKEHOLDERS AND SAME THING, I
GO TO RACHEL AND I'M LIKE I'M
Facebook ILLITERATE BUT HELP
ME MAKE SURE ON INSTAGRAM, ALL F
THESE WARES HELP ME FIND THEM
GET THE CHANNELS AND SHE GUIDES
ME AND LIKE I RECENTLY
DISCOVERED WHAT TO MAKE A REEL.
I HAD NO IDEA WHAT A REEL WAS.
AND YEAH Y'ALL CAN LAUGH AT ME,
THANK YOU, VERY MUCH BUT IT'S
THESE ONE-MINUTE MOVIES THAT
BASICALLY IN ONE MINUTE TELLING
YOU A NUGGET OF INFORMATION WITH
COOL MUSIC IN THE BACKGROUND AND
STUFF AND SO THIS IS, I HAD NO
IDEA WHAT THAT WAS.
THAT'S ALSO MAKING THE
INFORMATION IN THE FORMAT THAT
OUR FAMILIES WANT IT AND THEY'RE
LIKELY TO ACCESS IT.
SO I NEVER KNEW ABOUT ALL OF
THAT STUFF.
[LAUGHTER]
AND --
>> I JUST KNOW IT'S IMPORTANT TO
BE COMMUNICATING WITH THESE
ALONG THE WHOLE RESEARCH
PARADIGM.
SO, YES AT THE BEGINNING SO EVEN
WHEN YOU TALK ABOUT CREATING THE
STUDY THAT ANNOUNCING THE STUDY
AND TALKING ABOUT THE RESULTS
AND THE PROGRESS AS IT'S GOING
ON, NO ONE WANTS TO KNOW WHAT
HAPPENS FIVE YEARS LATER, RIGHT.
WE WANT TO KNOW AS IT'S
HAPPENING AND AS MUCH AS WE CAN
OBVIOUSLY AND YOU CAN'T PUBLISH
RESULTS BEFORE YOU CAN PUBLISH
THEM BUT WHAT CAN YOU TELL
STAKEHOLDERS AND PARTICIPANTS.
I THINK ANOTHER PIECE IS, THIS
IS SOMETHING THAT I GOT TAUGHT
VERY AEROMEX EARLY ON, IF YOU CN
EXPLAIN IN PLAIN LANGUAGE,
DOCTORS AND RESEARCHERS CAN
UNDERSTAND IT AS WELL.
YOU DON'T HAVE TO OVERCOME NOT
INDICATE THINGS, WE CAN
ALWAYS -- YOU DON'T NEED TO HAVE
TWO DIFFERENT TYPES OF LANGUAGE.
WE CAN ACTUALLY DO THIS AND WE
CAN ALL TALK THE SAME AND
OBVIOUSLY WHAT WE'RE DOING WITH
DATA ELEMENTS AND WHAT WE'RE
TRYING TO DO WITH MEETINGS LIKE
THIS TODAY IS DOING THAT IN I
THINK THAT'S THE BIGGEST PIECE.
HOW CAN WE KEEP OPEN
COMMUNICATION CHANNELS AND MEET
PEOPLE WHERE THEY'RE AT WHETHER
IT'S ON SOCIAL MEDIA OR THAT
PHYSICIANS OFFICE OR COMMUNITY
GROUPS.
AND YOU KNOW, TRYING TO TELL
PEOPLE AS MUCH AS POSSIBLE THAT
HEY, THERE'S AMAZING RESEARCH
GOING ON BECAUSE IT'S PART OF T
PEOPLE DON'T KNOW WHAT THEY
DON'T KNOW.
IF WE DON'T TELL PEOPLE, THEY
HAVE NO IDEA THAT ANY OF THIS
AMAZING WORK IS HAPPENING.
THAT'S ONE THING THAT I WOULD
TELL RESEARCHERS.
DON'T BE SCARED TO BLAST THAT
FROM THE ROOF TOPS.
>> SORRY.
I WANT TO ADD THAT I THINK
THAT'S BEEN A REALLY EXCITING
AND HONESTLY VERY GRATIFYING
PART OF THE GENOMICS WORK IS
THAT, AUTOMATIC THOUGH WE'RE
LOOKING AT IT FROM A BIG PICTUR,
30,000-FOOT FEW, EACH FAMILY IS
A PARTICIPANT AND STAKEHOLDER IN
OUR STUDY.
SO WE HAVE THE ABILITY THROUGH
THE GENOMICS WORK TO RETURN
RESULTS DIRECTLY TO FAMILIES
WITH THE CAVEAT THESE ARE
RESEARCH FINDINGS BUT THAT
OFFERS A UNIQUE OPPORTUNITY TO
ENGAGE WITH THOSE PARTICIPANTS
STAKEHOLDERS.
>> BUT THE THING WE CAN'T
FORGET, WE CAN'T WAIT, YOU KNOW,
10 TO 17 YEARS.
IF WE HAVE FINDINGS WE SHOW
THEY'RE SAFE AND EFFECTIVE WE
NEED TO TRANCE LATE THEM RIGHT
AWAY.
THE REASON RACHEL AND I DECIDED
ON THIS CONFERENCE WHERE IT'S
ALL IMPLEMENTATION WORKSHOPS, IS
WE'VE HAD ANDY GORDAN TALK AND
WE'VE HAD COOL INTERVENTIONS AND
TO TEACH OTHER PEOPLE
THERAPISTS, PHYSICIANS, EVERYONE
IN THE COMMUNITY SO WE START
CHANGING THE HEALTH-CARE SYSTEM
NOW, NOT IN 10 OR 17 YEARS, WITH
THE RESULTS OF ALL THIS
NIH-FUNDED RESEARCH AND WHEN I
SAID IT HAS TO BE IMPLEMENTABLE
IT'S NOT JUST DISSEMINATED OR
KNOWLEDGE TRANSLATION BUT IT'S
TRUE IMPLEMENTATION AND A
CHANGING OF THE HEALTH-CARE
SYSTEM.
YOU KNOW, WHAT NAHAL IS DOING IS
AMAZING AND I HOPE PEOPLE WILL
CHANGE IN NEURO RADIOLOGY BASED
ON THAT BUT IT WON'T JUST BE A
RESEARCH TOOL BUT A CLINICAL
TOOL.
>> YEAH, WE'RE WORKING ON
TRANSLATING IT AS WELL.
IN DEED.
I TOTALLY AGREE.
TAKES AWAY TOO LONG TO TRANSLATE
RESEARCH FINDINGS TO THE
BEDSIDE, THAT'S WHY, ESPECIALLY
SOME OF US THAT ARE CLINICIANS
NODE TO WORK EVEN HARDER TO
TRANSLATE IT.
>> Jim: I'M SURE THAT KATHY AND
BHOOMA WITH THEIR ANIMAL
STUDIES, THE MECHANISTIC STUDIES
SEE A LONGER TIMELINE THERE.
>> SO I THINK IF I COULD JUST
ADD TO THAT, IT'S SO VALUABLE
THINKING ABOUT TRANSLATION AND
WHAT THE TIMELINE IS AND I THINK
WHAT WE'RE SEEING MORE AND MORE
IS THIS KIND OF AGE-OLD CONCEPT
OF YOU START MECHANISTIC, YOU
THINK ABOUT A MODEL, COME UP
WITH THE TARGET.
DEVELOP A DRUG AND TEST THE DRUG
FOR SAFETY AND THEN YOU TAKE TO
PHASE 1, PHASE 2, PHASE 3 TRIALS
AND IT FEELS VERY LINEAR AND
THAT'S HOW I LEARNED ABOUT DID
IN TRAINING.
THAT THAT'S THE 10, 15, 30 YEAR
LONG PATH.
YOU I THINK CONFERENCES LIKE
THIS MAKE IT CLEAR WE SHOULD ALL
BE IN THE SAME ROOM TOGETHER
FROM THE BEGINNING AND THAT
FAMILIES, PEOPLE WITH CEREBRAL
PALSY, CLINICAL RESEARCHERS, THE
NIH, BASIC SCIENCE RESEARCHERS,
AND COME TOGETHER AND TALK ABOUT
OUR GOALS FROM THE OUTSIDE AND
INFORM WHAT WE'RE DOING IN EACH
OTHER'S LABS FROM THE OUTSIDE.
AND WE TRY VERY HARD TO DO THAT
IN THE LAB AND IN PART SOME OF
THE POWER OF BEING A PHYSICIAN
SCIENTIST OR HAVING PHYSICIAN IN
SCIENCE PARTNERS TOGETHER, IS
WHEN YOU ASSESS SOMETHING IN A
MOUSE OR A RABBIT OR YOUR ANIMAL
MODEL YOU CAN SAY, THIS IS HOW
WE CAN ASSESS THIS IN THE CLINIC
THEREFORE, FROM THE OUTSET AND
THE ANIMAL MOLD IS CLINICALLY
RELEVANT BECAUSE YOU ARE NOT
LOOKING FOR WHAT YOU THINK IN MY
CASE, DYSTONIA IS IN A MOUSE FRM
THE MODEL PERSPECTIVE BUT A
CLINICALLY RELATIVE PERSPECTIVE.
I'M PROUD THAT THAT IS THE
STANDARD AND WE'RE ALL IN THE
SAME ZOOM ROOM TOGETHER.
I DON'T THINK IT WOULD HAVE
ALWAYS BEEN THAT WAY OR IT'S NOT
HOW I WAS TOLD IT WAS AND I KIND
OF STARTED MY CAREER IN THE
FORMAT WHICH I'M VERY GRATEFUL
FOR.
>> THIS IS ALSO WHAT FAMILIES
ARE LOOKING FOR.
THIS IS NUMBER ONE QUESTION THEY
HAVE FOR ME, AS A CLINICAL
SCIENTIST, IS SO, IS THIS GOING
TO BE IN THE CLINIC?
IS THIS ACCESSIBLE OR NOT?
HOW DO YOU ANSWER THAT AT THE
BEGINNING OF EYE STUDY?
YOU ARE WORKING TOGETHER IN ELSE
IT OF UNDERSTANDING WHAT IS
HAPPENING.
I LIKE WHAT RACHEL SAID, YOU
CAN'T EXPLAIN WHAT IS HAPPENED
ACROSS THE CONTINUUM OF AN
ENTIRE STUDY BUT FOR EXAMPLE, IN
OUR LONGITUDINAL STUDY IT'S A
TWO-YEAR STUDY AND THEY'RE
COMING UP WITH THE FIRST TWO
YEARS LIFE.
WE HAVE A TRAVEL PASSPORTS,
TRAVEL THROUGH THE STUDY
PASSPORT AND UP STAMPS IN A BOOK
AND SHOWS THE CHANGE OVER TIME.
IT'S NOT GIVING AWAY THE RESULTS
OF A STUDY.
IT'S A JOURNEY TO SAY HOW CLOSE
ARE WE GETTING THIS INTO THE
CLINIC.
THIS IS WHERE WORE GOING RIGHT
NOW.
IT'S REALLY IMPORTANT PIECES TO
INVOLVE THE STAKEHOLDERS AND I
COMPLETE AGREE WITH BHOOMA IN
TERMS THAT WE NEED TO BE IN THE
SAME ROOM WHETHER IT'S ZOOM ROOM
OR NOT SO THANK YOU NIH FOR
BRINGING US TOGETHER IN THIS
MANNER.
>> Jim: WELL, IT'S OUR PLEASURE.
SO, I'M GOING TO SAY THANK YOU
TO YOU ALL FOR A WONDERFUL
AFTERNOON AND WONDERFUL MORNING.
IT'S BEEN A GREAT DIALOGUE AND I
HOPE THAT EVERYBODY IS ENJOYED
IT.
I'M GOING TO KICK OFFER TO MY
COLLEAGUE SAHANA KUKKE WHO WILL
WRAP IT UP FOR TODAY.
>> THANK YOU, JIM.
HELLO, MY NAM IS SAHANA AND I'M
A PROGRAM DIRECTOR FOR NEURAL
ENGINEERING AND NEURO TECHNOLOGY
RESEARCH AT NINDS AND IN THE
BRAIN INITIATIVE.
ON BEHALF OF THE PLANNING
COMMITTEE FOR THE CEREBRAL PALSY
WORKSHOP, THANK YOU TO ALL OUR
SPEAKERS FOR THESE STIMULATING
PRESENTATIONS AND TO AWFUL YOU
FOR THE ROBUST DISCUSSION ON
BASIC AND TRANSLATIONAL RESEARCH
TODAY.
WE HEARD FROM RACHEL BYRNE OF
THE CEREBRAL PALSY FOUNDATION
WHO INTRODUCED US TO THE
FOUNDATION'S STAKEHOLDER-DRIVEN
PERSPECTIVE ON MAKING CHANGE AND
CEREBRAL PALSY RESEARCH
INFRASTRUCTURE AND
IMPLEMENTATION, ADVOCACY AND
POLICY AND DISSEMINATION AND
EDUCATION.
AND WE HAD THE PLEASURE OF
HEARING FROM CAYDANCE ANDERSON
IN THE VOICE OF THE PARTICIPANT
WHO GRACIOUSLY SHARED HER
PERSONAL EXPERIENCES AS A YOUNG
WOMAN PARTICIPATING IN A
CEREBRAL PALSY REHABILITATION
RESEARCH STUDY.
SHE VOICED HER ROW MARKETABLE
COMMITMENT TO EDUCATING OTHERS
AND ENCOURAGING CHILDREN WITH
CEREBRAL PALSY WHO ARE YOUNGER
THAN SHE IS.
HER REMARKS PROVIDED AN
ESSENTIAL REFERENCE FRAME AND
INSPIRATION FOR OUR DISCUSSIONS
ON CEREBRAL PALSY RESEARCH.
WOAD PRESENTATIONS COVERING A
BROAD AND INTEGRATED RANGE OF
RESEARCH.
DEPENDING ON THE QUESTIONS
QUESTIONS BEING ASKED, DIFFERENT
ANIMAL MODELS CAN BE USEFUL IN
MOUSE PUPS IN CHARACTERIZING
DYSTONIA AND RABBIT KITS AFTER
WHITE MATTER INJURY.
IN HUMAN STUDIES WE HEARD ABOUT
A RANGE OF STUDY DESIGN
INCLUDING THE NF1 DESIGN AND
GENETIC NEURO DEVELOPMENTAL
DISORDERS AND PARENT-CHILD DYADS
AND NEWBORNS AND AGE RELEVANT
TASKS AND STIMULATION PARADIGMS
AND STUDIES.
ALTHOUGH WE HAVE COVERED AN
IMPRESSIVE RANGE OF TOPICS, AND
BASIC TRANSLATIONAL RESEARCH,
THERE REMAINS SOME GAPS.
SOME INCLUDE THE NEED FOR
LEARNING COHORTS FROM DIVERSE
BACKGROUNDS IN GENOMIC DATABASES
AND MORE SENSITIVE AND ABJECT
TIVE TESTS FOR MILD CEREBRAL
PALSY.
AND UNDERSTANDING DOSING WHEN
USING NEURO MODULATION
STRATEGIES AND OTHERS THAT MAY
HAVE COME TO YOUR BLI MIND.
WE HOPE IT MAKES PROGRESS AND
THROUGH FUTURE NIH GRANT
APPLICATIONS TO ADDRESS THE
GAPS.
A LARGE PREPORTION OF NIH
RESEARCH IS FUNDED THROUGH
INVESTIGATORS INITIATED HAPPEN
INDICATIONS AND WE ENCOURAGE YOU
TO CONSIDER RESEARCH PROPOSALS
TO BETTER UNDERSTAND HOW THE
BRAIN RECOVERS FROM PRE-NATAL
INSULTS AND PROMOTE RECOVERY AND
CEREBRAL PALSY.
THE NIH PROGRAM STAFF HERE TODAY
ARE HAPPY TO HELP GUIDE YOU
THROUGH THE APPLICATION PROCESS
SO PLEASE DON'T HESITATE TO
REACH OUT TO US.
TOMORROW, WE WILL MEET AGAIN FOR
DAY 2.
FROM 11:00 TO 4 :00 EASTERN TIME.
THE MAIN TOPICS FOR TOMORROW'S
SESSION ARE CLINICAL RESEARCH,
AND WORKFORCE AND RESOURCE
DEVELOPMENT.
SO GET YOUR QUESTIONS READY FOR
ANOTHER GREAT DISCUSSION.
YOU CAN USE THE SAME ZOOM
WEBINAR LINK YOU USED TODAY.
THANK YOU AGAIN FOR YOUR
PARTICIPATION AND WE'LL SEE YOU
TOMORROW.